Heteroaromatic macrocyclic ether chemotherapeutic agents

ABSTRACT

Disclosed are heterocyclic heteroaromatic macrocyclic ether compounds, pharmaceutically acceptable salts of the compounds and pharmaceutical compositions thereof. Also disclosed are methods of treating or preventing cancer using the heterocyclic heteroaromatic macrocyclic ether compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions thereof.

RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/US2021/030940, filed May 5, 2021; which claims the benefit ofpriority to International Patent Application No. PCT/CN2020/088589,filed May 5, 2020; and U.S. Provisional Patent Application Nos.63/125,747, filed Dec. 15, 2020; and 63/060,331, filed Aug. 3, 2020.

BACKGROUND

Receptor tyrosine kinases (RTKs) are cell surface enzymes that receiveoutside signals, such as whether to grow and divide, and transmit thosesignals in the cell through kinase activity. Many RTKs areproto-oncogenes; aberrant RTK activity can drive cell survival, growthand proliferation leading to cancer and related disorders. This aberrantkinase activity can be caused by mutations such as activating mutationsin the kinase domain, gene rearrangements that result in fusion proteinscontaining the intact kinase domain, amplification and other means. RTKproto-oncogenes include ROS1, anaplastic lymphoma kinase (ALK), NTRK1(encodes TRKA), NTRK2 (encodes TRKB), and NTRK3 (encodes TRKC).

ROS1 is an RTK proto-oncogene, with ROS1 rearrangements detected innon-small cell lung cancer (NSCLC), glioblastoma, inflammatorymyofibroblastic tumor (IMT), cholangiocarcinoma, ovarian cancer, gastriccancer, colorectal cancer, angiosarcoma, and spitzoid melanoma.Oncogenic ROS1 gene fusions contain the kinase domain of ROS1 (3′region) fused to the 5′ region of a variety of partner genes. Examplesof ROS1 fusion partner genes observed in NSCLC include SLC34A2, CD74,TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC, GPRC6A,LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17 (putative), SLMAP, SRSF6, TFG,TMEMI06B, TPD52L1, ZCCHC8 and CCDC6. Other fusion partners includeCAPRIN1, CEP85L, CHCHD3, CLIP1 (putative), EEF1G, KIF21A (putative),KLC1, SART3, ST13 (putative), TRIM24 (putative), ERC1, FTP1L1, HLAA,KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2,APOB, PLG, RBP4, and GOLGB1.

ALK is an RTK proto-oncogene, with ALK rearrangements detected in manycancers, including NSCLC, anaplastic large cell lymphoma (ALCL), IMT,diffuse large B-cell lymphoma (DLBCL), esophageal squamous cellcarcinoma (ESCC), renal medullary carcinoma, renal cell carcinoma,breast cancer, colon cancer, serous ovarian carcinoma, papillary thyroidcancer, and spitzoid tumors, and ALK activating mutations detected inneuroblastoma. Oncogenic ALK gene fusions contain the kinase domain ofALK (3′ region) fused to the 5′ region of more than 20 different partnergenes, the most common being EML4 in NSCLC and NPM in ALCL. Otherpartner genes include TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA,PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, DCTN1, SQSTM1, TPR,CRIM1, PTPN3, FBXO36, ATIC and KIFSB.

NTRK1, NTRK2 and NTRK3 are RTK proto-oncogenes that encode TRK-familykinases, with NTRK1, NTRK2 and NTRK3 chromosomal rearrangements detectedat low frequency in many cancers. For treatment of ROS1-positive orALK-positive patients, however, TRK inhibition, particularly in thecentral nervous system (CNS), has been associated with adversereactions, including dizziness/ataxia/gait disturbance, paraesthesia,weight gain and cognitive changes.

Agents in the prior art used to treat oncogenic ROS1 and ALK havesubstantial deficiencies. These deficiencies may represent one or moreof the following: associated TRK inhibition, limited CNS activity, andinadequate activity against resistance mutations. Treatment ofROS1-positive or ALK-positive patients accompanied by TRK inhibition isassociated with adverse reactions, particularly in the CNS, includingdizziness/ataxia/gait disturbance, paraesthesia, weight gain andcognitive changes. Additionally, there is a need for CNS-penetrant andTRK-sparing inhibitors of the wild type ROS1 kinase domain and ROS1 withacquired resistance mutations occurring either individually or incombination, including G2032R, D2033N, S1986F, S1986Y, L2026M, L1951R,E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G,F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, andL2086F. Likewise, there is a need for CNS-penetrant and TRK-sparinginhibitors of ALK with acquired resistance mutations. A variety of ALKdrug resistance mutations, occurring either individually or incombination, have been reported, including G1202R, L1196M, G1269A,C1156Y, I1171T, 11171N, I1171S, F1174L, V1180L, S1206Y, E1210K,1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q,L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V.

SUMMARY

An aspect disclosed herein are compounds of Formula (I) or apharmaceutically acceptable salt thereof:

wherein

Q is CH or N;

Z is CR₅ or N;

X is a 5-membered heteroarylene, comprising 1 to 3 heteroatoms selectedfrom the group consisting of nitrogen, sulfur and oxygen; wherein the5-membered heteroarylene is substituted with 0, 1, or 2 occurrences ofR₂;

Y is a heteroarylene selected from the group consisting of2*,3-substituted-furanylene, 2,3*-substituted-furanylene,3*,4-substituted-furanylene, 1*,2-substituted-imidazolylene,1*,5-substituted-imidazolylene, 1,5*-substituted-imidazolylene,4,5*-substituted-1,2,3-oxadiazolylene, 3,4*-substituted-1,2-oxazolylene,4*,5-substituted-1,2-oxazolylene, 4,5*-substituted-1,2-oxazolylene,4,5*-substituted-1,3-oxazolylene, 1*,2-substituted-phenylene,1,5*-substituted-pyrazolylene, 4*,5-substituted-pyrazolylene,3,4*-substituted-pyridazinylene, 4*,5-substituted-pyridazinylene,2,3*-substituted-pyridinylene, 3*,4-substituted-pyridinylene,3,4*-substituted-pyridinylene, 4,5*-substituted-pyrimidinylene,1*,2-substituted-pyrrolylene, 1,2*-substituted-pyrrolylene,2,3*-substituted-pyrrolylene, 3*,4-substituted-pyrrolylene,4,5*-substituted-1,2,3-thiadiazolylene,3,4*-substituted-1,2-thiazolylene, 4*,5-substituted-1,2-thiazolylene,4,5*-substituted-1,2,3-thiadiazolylene,3,4*-substituted-1,2-thiazolylene, 4*,5-substituted-1,2-thiazolylene,4,5*-substituted-1,2-thiazolylene, 4,5*-substituted-1,3-thiazolylene,2*,3-substituted-thiophenylene, 2,3*-substituted-thiophenylene,3*,4-substituted-thiophenylene, 4,5*-substituted-1,2,3-triazinylene,1,5*-substituted-1,2,3-triazolylene, and3,4*-substituted-1,2,4-triazolylene; wherein the heteroarylene issubstituted with 0, 1, or 2 occurrences of R₃;

* indicates the point of attachment of X or Y to the methylene groupbonded to X and Y;

in Y the heteroarylene ring atom alpha to the point of attachment to themethylene group and beta to the point of attachment to the aromatic ringcomprising Z is carbon, oxygen, or sulfur;

R₁ is selected from the group consisting of H, methyl, andhydroxymethyl;

each instance of R₂ is independently selected from the group consistingof CN, halo, C₁₋₄ alkoxy, C₁₋₄ alkyl, halo-C₁₋₄ alkyl, C₃₋₄cycloalkylmethyl, C₃₋₆ cycloalkyl, and C₃₋₆ heterocyclyl;

each instance of R₃ is independently selected from the group consistingof H, halo, CN, C₁₋₄ alkoxy, halo-C₁₋₄ alkyl, and C₁₋₄ alkyl; and

each of R₄ and R₅ is independently H or F;

provided that the compound is not

In certain embodiments, the present disclosure provides a pharmaceuticalcomposition suitable for use in a subject in the treatment or preventionof cancer comprising an effective amount of any of the compoundsdescribed herein (e.g., a compound of the disclosure, such as a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, and oneor more pharmaceutically acceptable excipients. In certain embodiments,the pharmaceutical preparations may be for use in treating or preventinga condition or disease as described herein.

An aspect of the disclosure is methods of treating cancer that ischaracterized by one or more mutations in the ROS1 or ALK genes,comprising administering to a subject in need thereof an effectiveamount of a compound as disclosed herein (e.g., a compound of Formula(I) or any of the embodiments thereof disclosed herein). In certainembodiments the compound is an inhibitor of ROS1, other embodiments thecompound is an inhibitor of ALK, in additional embodiments the compoundis an inhibitor of ROS1 and ALK. In certain aspects, the human subjectis in need of such treatment.

These cancers include, but are not limited to, non-small cell lungcancer, inflammatory myofibroblastic tumor, ovarian cancer, spitzoidmelanoma, glioblastoma, cholangiocarcinoma, gastric cancer, colorectalcancer, angiosarcoma, anaplastic large cell lymphoma, diffuse largeB-cell lymphoma, esophageal squamous cell carcinoma, renal medullarycarcinoma, renal cell carcinoma, breast cancer, papillary thyroidcancer, and neuroblastoma.

In some embodiments, the method of treating or preventing cancer maycomprise administering a compound of Formula (I) conjointly with one ormore other chemotherapeutic agent(s).

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by a person skilled in the art ofthe present disclosure. The following references provide one of skillwith a general definition of many of the terms used in this disclosure:Singleton et al., Dictionary of Microbiology and Molecular Biology (2nded. 1994); The Cambridge Dictionary of Science and Technology (Walkered., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.),Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionaryof Biology (1991). As used herein, the following terms have the meaningsascribed to them below, unless specified otherwise.

In some embodiments, chemical structures are disclosed with acorresponding chemical name. In case of conflict, the chemical structurecontrols the meaning, rather than the name.

In this disclosure, “comprises,” “comprising,” “containing” and “having”and the like can have the meaning ascribed to them in U.S. Patent lawand can mean “includes,” “including,” and the like; “consistingessentially of” or “consists essentially” likewise has the meaningascribed in U.S. Patent law and the term is open-ended, allowing for thepresence of more than that which is recited so long as basic or novelcharacteristics of that which is recited are not substantially changedby the presence of more than that which is recited, but excludes priorart embodiments.

Unless specifically stated or obvious from context, as used herein, theterm “or” is understood to be inclusive. Unless specifically stated orobvious from context otherwise, as used herein, the terms “a”, “an”, and“the” are understood to be singular or plural.

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbylC(O)—, preferably alkylC(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbylC(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group, preferably a lower alkylgroup, having an oxygen attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond and is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed below, except where stability isprohibitive. For example, substitution of alkenyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

An “alkyl” group or “alkane” is a straight chained or branchednon-aromatic hydrocarbon which is completely saturated. Typically, astraight chained or branched alkyl group has from 1 to about 20 carbonatoms, preferably from 1 to about 10 unless otherwise defined. Examplesof straight chained and branched alkyl groups include methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl,pentyl and octyl. A C1-C₆ straight chained or branched alkyl group isalso referred to as a “lower alkyl” group.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing a hydrogen on oneor more carbons of the hydrocarbon backbone. Such substituents, if nototherwise specified, can include, for example, a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl),a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, anamino, an amido, an amidine, an imine, a cyano, a nitro, an azido, asulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, asulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic orheteroaromatic moiety. It will be understood by those skilled in the artthat the moieties substituted on the hydrocarbon chain can themselves besubstituted, if appropriate. For instance, the substituents of asubstituted alkyl may include substituted and unsubstituted forms ofamino, azido, imino, amido, phosphoryl (including phosphonate andphosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl andsulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls(including ketones, aldehydes, carboxylates, and esters), —CF₃, —CN andthe like. Exemplary substituted alkyls are described below. Cycloalkylscan be further substituted with alkyls, alkenyls, alkoxys, alkylthios,aminoalkyls, carbonyl-substituted alkyls, —CF₃, —CN, and the like.

The term “C_(x-y)” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups that contain from x to y carbons in the chain. Forexample, the term “C_(x-y)alkyl” refers to substituted or unsubstitutedsaturated hydrocarbon groups, including straight-chain alkyl andbranched-chain alkyl groups that contain from x to y carbons in thechain, including haloalkyl groups such as trifluoromethyl and2,2,2-tirfluoroethyl, etc. C₀ alkyl indicates a hydrogen where the groupis in a terminal position, a bond if internal. The terms“C_(2-y)alkenyl” and “C_(2-y)alkynyl” refer to substituted orunsubstituted unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double or triple bond respectively.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkylS—.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing a hydrogen onone or more carbons of the alkynyl group. Such substituents may occur onone or more carbons that are included or not included in one or moretriple bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed above, except where stability isprohibitive. For example, substitution of alkynyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “amide”, as used herein, refers to a group

wherein each R³⁰ independently represents a hydrogen or hydrocarbylgroup, or two R³⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein each R³¹ independently represents a hydrogen or a hydrocarbylgroup, or two R³¹ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure. The term “aminoalkyl”, as used herein, refers to an alkylgroup substituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group.

The term “aryl” as used herein include substituted or unsubstitutedsingle-ring aromatic groups in which each atom of the ring is carbon.Preferably, the ring is a 5- to 7-membered ring, more preferably a6-membered ring. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings is aromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groupsinclude benzene, naphthalene, phenanthrene, phenol, aniline, and thelike.

The term “carbamate” is art-recognized and refers to a group

wherein R³² and R³³ independently represent hydrogen or a hydrocarbylgroup, such as an alkyl group, or R³² and R³³ taken together with theintervening atom(s) complete a heterocycle having from 4 to 8 atoms inthe ring structure.

The terms “carbocycle”, and “carbocyclic”, as used herein, refers to asaturated or unsaturated ring in which each atom of the ring is carbon.The term carbocycle includes both aromatic carbocycles and non-aromaticcarbocycles. Non-aromatic carbocycles include both cycloalkane rings, inwhich all carbon atoms are saturated, and cycloalkene rings, whichcontain at least one double bond.

The term “carbocycle” includes 5-7 membered monocyclic and 8-12 memberedbicyclic rings. Each ring of a bicyclic carbocycle may be selected fromsaturated, unsaturated and aromatic rings. Carbocycle includes bicyclicmolecules in which one, two or three or more atoms are shared betweenthe two rings. The term “fused carbocycle” refers to a bicycliccarbocycle in which each of the rings shares two adjacent atoms with theother ring. Each ring of a fused carbocycle may be selected fromsaturated, unsaturated and aromatic rings. In an exemplary embodiment,an aromatic ring, e.g., phenyl, may be fused to a saturated orunsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Anycombination of saturated, unsaturated and aromatic bicyclic rings, asvalence permits, is included in the definition of carbocyclic. Exemplary“carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane,1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene,bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fusedcarbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene,bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene andbicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one ormore positions capable of bearing a hydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completelysaturated. “Cycloalkyl” includes monocyclic and bicyclic rings.Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbonatoms, more typically 3 to 8 carbon atoms unless otherwise defined. Thesecond ring of a bicyclic cycloalkyl may be selected from saturated,unsaturated and aromatic rings. Cycloalkyl includes bicyclic moleculesin which one, two or three or more atoms are shared between the tworings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl inwhich each of the rings shares two adjacent atoms with the other ring.The second ring of a fused bicyclic cycloalkyl may be selected fromsaturated, unsaturated and aromatic rings. A “cycloalkenyl” group is acyclic hydrocarbon containing one or more double bonds.

The term “carbocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a carbocycle group.

The term “C₃₋₄ cycloalkylmethyl”, as used herein, refers to a methylgroup substituted with a carbocycle group containing 3 to 4 carbonatoms.

The term “carbonate” is art-recognized and refers to a group —OCO₂—R³⁴,wherein R³⁴ represents a hydrocarbyl group.

The term “carboxy”, as used herein, refers to a group represented by theformula —CO₂H.

The term “ester”, as used herein, refers to a group —C(O)OR³⁵ whereinR³⁵ represents a hydrocarbyl group.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The terms “halo” and “halogen” as used herein means halogen and includeschloro, fluoro, bromo, and iodo.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a hetaryl group.

The term “heteroalkyl”, as used herein, refers to a saturated orunsaturated chain of carbon atoms and at least one heteroatom, whereinno two heteroatoms are adjacent.

The terms “heteroaryl” and “hetaryl” include substituted orunsubstituted aromatic single ring structures, preferably 5- to7-membered rings, more preferably 5- to 6-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and “hetaryl” also include polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings wherein at least one of the rings is heteroaromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroarylgroups include, for example, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, andpyrimidine, and the like.

The asterisk (*) notation on a heteroarylene ring moiety correspondingto X or Y in the compound of Formula (I) identifies the ring atom of themoiety bonded to the methylene group between X and Y, as exemplifiedbelow:

For example, “1*,5-substituted-imidazolylene” for Y means substituted:

IUPAC numbering rules for heteroarylene rings are used throughout thespecification to designate ring atom positions, as shown above. In thisexample, the 1-position of the imidazolylene is bonded to the methylenegroup, so it is indicated with the asterisk. The asterisk notation isused in both the names and structures of heteroarylenes for X and Y.Here, for Y the ring atom at the 5-position is not marked because it'sbound to the phenyl group bearing variable R₄.

For X, an exemplary ring would be “1,5*-substituted-imidazolylene” asshown below.

The ring atom bound to the methylene group (the 5-position in thisexample) is indicated with the asterisk in both the names and structuresof ring X heteroarylenes. The ring atom bonded to the aromatic ringbearing Q is not marked.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, andsulfur.

The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer tosubstituted or unsubstituted non-aromatic ring structures, preferably 3-to 10-membered rings, more preferably 3- to 7-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heterocyclyl” and “heterocyclic” also include polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings isheterocyclic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.Heterocyclyl groups include, for example, piperidine, piperazine,pyrrolidine, morpholine, lactones, lactams, and the like.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group.

The term “hydrocarbyl”, as used herein, refers to a group that is bondedthrough a carbon atom that does not have a ═O or ═S substituent, andtypically has at least one carbon-hydrogen bond and a primarily carbonbackbone, but may optionally include heteroatoms. Thus, groups likemethyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to behydrocarbyl for the purposes of this application, but substituents suchas acetyl (which has a ═O substituent on the linking carbon) and ethoxy(which is linked through oxygen, not carbon) are not. Hydrocarbyl groupsinclude, but are not limited to aryl, heteroaryl, carbocycle,heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group.

The term “lower” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups where there are ten or fewer non-hydrogen atoms in thesubstituent, preferably six or fewer. A “lower alkyl”, for example,refers to an alkyl group that contains ten or fewer carbon atoms,preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl,alkenyl, alkynyl, or alkoxy substituents defined herein are respectivelylower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, orlower alkoxy, whether they appear alone or in combination with othersubstituents, such as in the recitations hydroxyalkyl and aralkyl (inwhich case, for example, the atoms within the aryl group are not countedwhen counting the carbon atoms in the alkyl substituent).

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two ormore rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls) in which two or more atoms are commonto two adjoining rings, e.g., the rings are “fused rings”. Each of therings of the polycycle can be substituted or unsubstituted. In certainembodiments, each ring of the polycycle contains from 3 to 10 atoms inthe ring, preferably from 5 to 7.

The term “silyl” refers to a silicon moiety with three hydrocarbylmoieties attached thereto.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes the implicit provisothat such substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and non-aromaticsubstituents of organic compounds. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. Substituents can include any substituents described herein,for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that substituents canthemselves be substituted, if appropriate. Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understoodto include substituted variants. For example, reference to an “aryl”group or moiety implicitly includes both substituted and unsubstitutedvariants.

The term “sulfate” is art-recognized and refers to the group —OSO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R³⁶ and R³⁷ independently represent hydrogen or hydrocarbyl,such as alkyl, or R³⁶ and R³⁷ taken together with the interveningatom(s) complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “sulfoxide” is art-recognized and refers to the group—S(O)—R³⁸, wherein R³⁸ represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfone” is art-recognized and refers to the group —S(O)₂—R³⁹,wherein R³⁹ represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thioester”, as used herein, refers to a group —C(O)SR⁴⁰ or—SC(O)R⁴⁰ wherein R¹⁰ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R⁴¹ and R⁴² independently represent hydrogen or a hydrocarbyl,such as alkyl, or either occurrence of R⁴¹ taken together with R⁴² andthe intervening atom(s) complete a heterocycle having from 4 to 8 atomsin the ring structure.

The term “protecting group” refers to a group of atoms that, whenattached to a reactive functional group in a molecule, mask, reduce orprevent the reactivity of the functional group. Typically, a protectinggroup may be selectively removed as desired during the course of asynthesis. Examples of protecting groups can be found in Greene andWuts, Protective Groups in Organic Chemistry, 3^(rd) Ed., 1999, JohnWiley & Sons, NY and Harrison et al., Compendium of Synthetic OrganicMethods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representativenitrogen protecting groups include, but are not limited to, formyl,acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”),tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”),2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxylprotecting groups include, but are not limited to, those where thehydroxyl group is either acylated (esterified) or alkylated such asbenzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranylethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers,such as ethylene glycol and propylene glycol derivatives and allylethers.

In certain embodiments, compounds of the disclosure may be racemic. Incertain embodiments, compounds of the disclosure may be enriched in oneenantiomer. For example, a compound of the disclosure may have greaterthan about 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70%ee, about 80% ee, about 90% ee, or even about 95 or greater ee. Incertain embodiments, compounds of the disclosure may have more than onestereocenter. In certain such embodiments, compounds of the disclosuremay be enriched in one or more diastereomer. For example, a compound ofthe disclosure may have greater than about 30% de, about 40% de, about50% de, about 60% de, about 70% de, about 80% de, about 90% de, or evenabout 95 or greater de.

In certain embodiments, the therapeutic preparation may be enriched toprovide predominantly one enantiomer of a compound (e.g., of Formula(I)). An enantiomerically enriched mixture may comprise, for example, atleast about 60 mol percent of one enantiomer, or more preferably atleast about 75, about 90, about 95, or even about 99 mol percent. Incertain embodiments, the compound enriched in one enantiomer issubstantially free of the other enantiomer, wherein substantially freemeans that the substance in question makes up less than about 10%, orless than about 5%, or less than about 4%, or less than about 3%, orless than about 2%, or less than about 1% as compared to the amount ofthe other enantiomer, e.g., in the composition or compound mixture. Forexample, if a composition or compound mixture contains about 98 grams ofa first enantiomer and about 2 grams of a second enantiomer, it would besaid to contain about 98 mol percent of the first enantiomer and onlyabout 2 of the second enantiomer.

In certain embodiments, the therapeutic preparation may be enriched toprovide predominantly one diastereomer of a compound (e.g., of Formula(I)). A diastereomerically enriched mixture may comprise, for example,at least about 60 mol percent of one diastereomer, or more preferably atleast about 75, about 90, about 95, or even about 99 mol percent.

In some embodiments, a moiety in a compound exists as a mixture oftautomers. A “tautomer” is a structural isomer of a moiety or a compoundthat readily interconverts with another structural isomer. For example,a pyrazole ring has two tautomers:

which differ in the positions of the pi-bonds and a hydrogen atom.Unless explicitly stated otherwise, a drawing of one tautomer of amoiety or a compound encompasses all of the possible tautomers.

The term “subject” to which administration is contemplated includes, butis not limited to, humans (i.e., a male or female of any age group,e.g., a pediatric subject (e.g., infant, child, adolescent) or adultsubject (e.g., young adult, middle-aged adult or senior adult)) and/orother primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals,including commercially relevant mammals such as cattle, pigs, horses,sheep, goats, cats, and/or dogs; and/or birds, including commerciallyrelevant birds such as chickens, ducks, geese, quail, and/or turkeys.Preferred subjects are humans.

As used herein, a therapeutic that “prevents” a disorder or conditionrefers to a compound that, in a statistical sample, reduces theoccurrence of the disorder or condition in the treated sample relativeto an untreated control sample, or delays the onset or reduces theseverity of one or more symptoms of the disorder or condition relativeto the untreated control sample. These effects are also called“prophylactic” effects. Thus, as used herein and unless otherwisespecified, the terms “prevention” and “preventing” refer to an approachfor obtaining beneficial or desired results including, but not limited,to prophylactic benefit. For prophylactic benefit, a therapeutic can beadministered to a patient at risk of developing a particular disease, orto a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.In one embodiment, a therapeutic is administered prior to clinicalmanifestation of the unwanted condition (e.g., disease or other unwantedstate of the subject) for prophylactic benefit (e.g., it protects thesubject against developing the unwanted condition).

As used herein and unless otherwise specified, the terms “treatment” and“treating” refer to therapeutic or palliative measures. Beneficial ordesired clinical results include, but are not limited to, alleviation,in whole or in part, of symptoms associated with a disease or disorderor condition, diminishment of the extent of disease, stabilized (i.e.,not worsening) state of disease, delay or slowing of diseaseprogression, amelioration or palliation of the disease state (e.g., oneor more symptoms of the disease), and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. In one embodiment, “treatment” comprises administration of atherapeutic after manifestation of the unwanted condition (i.e., it isintended to diminish, ameliorate, or stabilize the existing unwantedcondition or side effects thereof).

The term “prodrug” is intended to encompass compounds which, underphysiologic conditions, are converted into the therapeutically activeagents of the present disclosure (e.g., a compound of Formula (I)). Acommon method for making a prodrug is to include one or more selectedmoieties which are hydrolyzed under physiologic conditions to reveal thedesired molecule. In other embodiments, the prodrug is converted by anenzymatic activity of the subject. For example, esters or carbonates(e.g., esters or carbonates of alcohols or carboxylic acids) arepreferred prodrugs of the present disclosure. In certain embodiments,some or all of the compounds of Formula (I) in a formulation representedabove can be replaced with the corresponding suitable prodrug, e.g.,wherein a hydroxyl in the parent compound is presented as an ester or acarbonate or carboxylic acid.

An “effective amount”, as used herein, refers to an amount that issufficient to achieve a desired biological effect. A “therapeuticallyeffective amount”, as used herein, refers to an amount that issufficient to achieve a desired therapeutic effect. For example, atherapeutically effective amount can refer to an amount that issufficient to improve at least one sign or symptom of cancer.

A “response” to a method of treatment can include a decrease in oramelioration of negative symptoms, a decrease in the progression of adisease or symptoms thereof, an increase in beneficial symptoms orclinical outcomes, a lessening of side effects, stabilization ofdisease, partial or complete remedy of disease, among others.

As used herein and unless otherwise indicated, the term “relapsed”refers to a disorder, disease, or condition that responded to priortreatment (e.g., achieved a complete response) then had progression. Theprior treatment can include one or more lines of therapy.

As used herein and unless otherwise indicated, the term “refractory”refers to a disorder, disease, or condition that has not responded toprior treatment that can include one or more lines of therapy.

Compounds

In one aspect, provided herein is a compound of Formula (I), or anenantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof:

wherein

Q is CH or N;

Z is CR₅ or N;

X is a 5-membered heteroarylene, comprising 1 to 3 heteroatoms selectedfrom the group consisting of nitrogen, oxygen and sulfur; wherein the5-membered heteroarylene is substituted with 0, 1, or 2 occurrences ofR₂;

Y is a 5- or 6-membered heteroarylene, comprising 1 to 3 heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur;wherein the 5- or 6-membered heteroarylene is substituted with 0, 1, or2 occurrences of R₃;

in Y, the point of attachment to the methylene group bonded to X and Yand the point of attachment to the aromatic ring comprising Z are onadjacent atoms, and the 5- or 6-membered heteroarylene ring atom alphato the point of attachment to the methylene group and beta to the pointof attachment to the aromatic ring comprising Z is carbon, oxygen, orsulfur;

R₁ is selected from the group consisting of H, methyl, andhydroxymethyl; each instance of R₂ is independently selected from thegroup consisting of H, CN, halo, C₁₋₄ alkoxy, C₁₋₄ alkyl, halo-C₁₋₄alkyl, C₃₋₄ cycloalkylmethyl, C₃₋₆ cycloalkyl, and C₃₋₆ heterocyclyl;

each instance of R₃ is independently selected from the group consistingof H, halo, CN, C₁₋₄ alkoxy, halo-C₁₋₄ alkyl, and C₁₋₄ alkyl; and

each of R₄ and R₅ is independently H or F;

provided that X is not 3*,4-substituted-pyrazolylene, where * indicatesthe point of attachment of X or Y to the methylene group bonded to X andY.

In one aspect, disclosed is a compound of Formula (I) or apharmaceutically acceptable salt thereof:

wherein

Q is CH or N;

Z is CR₅ or N;

X is a 5-membered heteroarylene, comprising 1 to 3 heteroatoms selectedfrom the group consisting of nitrogen, sulfur and oxygen; wherein the5-membered heteroarylene is substituted with 0, 1, or 2 occurrences ofR₂;

Y is a heteroarylene selected from the group consisting of2*,3-substituted-furanylene, 2,3*-substituted-furanylene,3*,4-substituted-furanylene, 1*,2-substituted-imidazolylene,1*,5-substituted-imidazolylene, 1,5*-substituted-imidazolylene,4,5*-substituted-1,2,3-oxadiazolylene, 3,4*-substituted-1,2-oxazolylene,4*,5-substituted-1,2-oxazolylene, 4,5*-substituted-1,2-oxazolylene,4,5*-substituted-1,3-oxazolylene, 1*,2-substituted-phenylene,1,5*-substituted-pyrazolylene, 4*,5-substituted-pyrazolylene,3,4*-substituted-pyridazinylene, 4*,5-substituted-pyridazinylene,2,3*-substituted-pyridinylene, 3*,4-substituted-pyridinylene,3,4*-substituted-pyridinylene, 4,5*-substituted-pyrimidinylene,1*,2-substituted-pyrrolylene, 1,2*-substituted-pyrrolylene,2,3*-substituted-pyrrolylene, 3*,4-substituted-pyrrolylene,4,5*-substituted-1,2,3-thiadiazolylene,3,4*-substituted-1,2-thiazolylene, 4*,5-substituted-1,2-thiazolylene,4,5*-substituted-1,2-thiazolylene, 4,5*-substituted-1,3-thiazolylene,2*,3-substituted-thiophenylene, 2,3*-substituted-thiophenylene,3*,4-substituted-thiophenylene, 4,5*-substituted-1,2,3-triazinylene,1,5*-substituted-1,2,3-triazolylene, and3,4*-substituted-1,2,4-triazolylene; wherein the heteroarylene issubstituted with 0, 1, or 2 occurrences of R₃;

* indicates the point of attachment of X or Y to the methylene groupbonded to X and Y;

in Y the heteroarylene ring atom alpha to the point of attachment to themethylene group and beta to the point of attachment to the aromatic ringcomprising Z is carbon, oxygen, or sulfur;

R₁ is selected from the group consisting of H, methyl, andhydroxymethyl;

each instance of R₂ is independently selected from the group consistingof H, CN, halo, C₁₋₄ alkoxy, C₁₋₄ alkyl, halo-C₁₋₄ alkyl, C₃₋₄cycloalkylmethyl, C₃₋₆ cycloalkyl, and C₃₋₆ heterocyclyl;

each instance of R₃ is independently selected from the group consistingof H, halo, CN, C₁₋₄ alkoxy, halo-C₁₋₄ alkyl, and C₁₋₄ alkyl; and

each of R₄ and R₅ is independently H or F;

provided that the compound is not

In some embodiments, X is a 5-membered heteroaryl selected from thegroup consisting of pyrazolylene, isoxazolylene, isothiazolylene,imidazolylene, and triazolylene. In some embodiments, X is selected fromthe group consisting of pyrazolylene and triazolylene. In certainembodiments, X is selected from the group consisting of4*,5-substituted-pyrazolylene, 4,5*-substituted-pyrazolylene,1*,5-substituted-pyrazolylene, 4*,5-substituted-isoxazolylene,3*,4-substituted-isoxazolylene, 3*,4-substituted-isothiazolylene,4*,5-substituted-isothiazolylene, 4*,5-substituted-imidazolylene,1*,5-substituted-imidazolylene, 1*,5-substituted-triazolylene, and4*,5-substituted-triazolylene.

In some embodiments, X is a 5-membered heteroaryl selected from thegroup consisting of pyrazolylene, isoxazolylene, isothiazolylene,imidazolylene, and triazolylene. In some embodiments, X is selected fromthe group consisting of pyrazolylene and triazolylene. In certainembodiments, X is selected from the group consisting of4*,5-substituted-pyrazolylene, 4,5*-substituted-pyrazolylene,1*,5-substituted-pyrazolylene, 4*,5-substituted-isoxazolylene,4,5*-substituted-isoxazolylene, 3*,4-substituted-isoxazolylene,3*,4-substituted-isothiazolylene, 4*,5-substituted-isothiazolylene,4,5*-substituted-isothiazolylene, 4*,5-substituted-imidazolylene,1*,5-substituted-imidazolylene, 1*,5-substituted-triazolylene, and4*,5-substituted-triazolylene.

In certain embodiments, X is selected from the group consisting of:

* indicates the point of attachment of X to the methylene group bondedto X and Y; and

R₂ is independently selected from the group consisting of H, CN, halo,C₁₋₄ alkoxy, C₁₋₄ alkyl, halo-C₁₋₄ alkyl, C₃₋₄ cycloalkylmethyl, C₃₋₆cycloalkyl, and C₃₋₆ heterocyclyl.

In one embodiment, X is a pyrazolylene. In one embodiment, X is not3*,4-substituted-pyrazolylene. In one embodiment, X is not

In one embodiment, X is not

In another embodiment, X is 3*,4-substituted-pyrazolylene. In anotherembodiment, X is 4*,5-substituted-pyrazolylene. In another embodiment, Xis 4,5*-substituted-pyrazolylene. In another embodiment, X is1*,5-substituted-pyrazolylene. In one embodiment, X is

In one embodiment, X is

In one embodiment, X is

In one embodiment, X is isoxazolylene. In one embodiment, X is4*,5-substituted-isoxazolylene. In one embodiment, X is4,5*-substituted-isoxazolylene. In one embodiment, X is3*,4-substituted-isoxazolylene. In one embodiment, X is

In one embodiment, X is

In one embodiment, X is isothiazolylene. In one embodiment, X is3*,4-substituted-isothiazolylene. In one embodiment, X is4*,5-substituted-isothiazolylene. In one embodiment, X is4,5*-substituted-isothiazolylene. In one embodiment, X is

In one embodiment, X is

In one embodiment, X is imidazolylene. In one embodiment, X is4*,5-substituted-imidazolylene. In one embodiment, X is1*,5-substituted-imidazolylene. In one embodiment, X is

In one embodiment, X is triazolylene. In one embodiment, X is1*,5-substituted-triazolylene. In one embodiment, X is4*,5-substituted-triazolylene. In one embodiment, X is

In one embodiment, X is

In one embodiment, X is substituted with 0 occurrence of R₂ (i.e., allopen positions on X are H). In one embodiment, X is substituted with 1occurrence of R₂ that is not H. In one embodiment, X is substituted with2 occurrences of R₂ that are not H.

R₂ is independently selected from the group consisting of H, halo, CN,C₁₋₄ alkoxy, C₁₋₄ alkyl, halo-C₁₋₄ alkyl, C₃₋₄ cycloalkylmethyl, C₃₋₆cycloalkyl, and C₃₋₆ heterocycloalkyl. In one embodiment, R₂ is not H.In one embodiment, R₂ is C₁₋₄ alkyl. In one embodiment, R₂ is methyl. Inone embodiment, R₂ is ethyl. In one embodiment, R₂ is isopropyl. In oneembodiment, R₂ is cyclopropyl. In one embodiment, R₂ is cyclobutyl. Inone embodiment, R₂ is cyclopropylmethyl. In one embodiment, R₂ is —CHF₂.In one embodiment, R₂ is —CH₂CHF₂. In one embodiment, R₂ is halo. In oneembodiment, R₂ is fluoro. In one embodiment, R₂ is chloro. In oneembodiment, R₂ is CN. In one embodiment, R₂ is methoxy.

In certain embodiments, X is selected from the group consisting of:

In some embodiments, Y is selected from the group consisting of4*,5-substituted pyrazolylene, 1,5*-substituted pyrazolylene,3,4*-substituted pyrazolylene, 1*,2-substituted imidazolylene,5*,1-substituted imidazolylene, 4,5*-substituted 1,3-thiazolylene,3,4*-substituted 1,2-oxazolylene, 4*,5-substituted 1,2-oxazolylene,3,4*-substituted 1,2-thiazolylene, 4*,5-substituted 1,2-thiazolylene,2,3*-substituted pyridinylene, 3*,4-substituted pyridinylene,4*,3-substituted pyridinylene, 4,5*-substituted pyrimidinylene,1,5*-substituted 1,2,3-triazolylene, and 3,4*-substituted1,2,4-triazolylene.

In certain embodiments, Y is selected from the group consisting of

* indicates the point of attachment of Y to the methylene group bondedto X and Y; and

R₃ is selected from the group consisting of H, halo, CN, C₁₋₄alkoxy,halo-C₁₋₄ alkyl, and C₁₋₄ alkyl.

In one embodiment, Y is a 5-membered heteroarylene. In one embodiment, Yis pyrazolylene. In one embodiment, Y is 1,5*-substituted pyrazolylene.In one embodiment, Y is 4*,5-substituted pyrazolylene. In oneembodiment, Y is 3,4*-substituted pyrazolylene. In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is imidazolylene. In one embodiment, Y is1*,2-substituted imidazolylene. In one embodiment, Y is 5*,1-substitutedimidazolylene. In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is 1,2-thiazolylene. In one embodiment, Y is3,4*-substituted 1,2-thiazolylene. In one embodiment, Y is4*,5-substituted 1,2-thiazolylene. In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is 1,3-thiazolylene. In one embodiment, Y is4,5*-substituted 1,3-thiazolylene. In one embodiment, Y is

In one embodiment, Y is 1,2-oxazolylene. In one embodiment, Y is3,4*-substituted 1,2-oxazolylene. In one embodiment, Y is4*,5-substituted 1,2-oxazolylene. In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is triazolylene. In one embodiment, Y is1,5*-substituted 1,2,3-triazolylene. In one embodiment, Y is3,4*-substituted 1,2,4-triazolylene. In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is a 6-membered heteroarylene. In one embodiment, Yis pyridinylene. In one embodiment, Y is 2,3*-substituted pyridinylene.In one embodiment, Y is 3*,4-substituted pyridinylene. In oneembodiment, Y is 4*,3-substituted pyridinylene. In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is

In one embodiment, Y is pyrimidinylene. In one embodiment, Y is4,5*-substituted pyrimidinylene. In one embodiment, Y is

In one embodiment, Y is substituted with 0 occurrence of R₃ (i.e., allopen positions on Y are H). In one embodiment, Y is substituted with 1occurrence of R₃ that is not H. In one embodiment, Y is substituted with2 occurrences of R₃ that are not H.

In one embodiment, R₃ is selected from the group consisting of H, halo,CN, C₁₋₄ alkoxy, halo-C₁₋₄ alkyl, and C₁₋₄ alkyl. In one embodiment, R₃is not H. In one embodiment, R₃ is C₁₋₄ alkyl. In one embodiment, R₃ ismethyl. In one embodiment, R₃ is ethyl. In one embodiment, R₃ is halo.In one embodiment, R₃ is flouro. In one embodiment, R₃ is chloro. In oneembodiment, R₃ is CN.

In one embodiment, X is a pyrazolylene provided herein (e.g., a4*,5-substituted-pyrazolylene provided herein), and Y is a pyrazolyleneprovided herein. In another embodiment, Y is an imidazolylene providedherein. In another embodiment, Y is a 1,2-thiazolylene provided herein.In another embodiment, Y is a 1,3-thiazolylene provided herein. Inanother embodiment, Y is a 1,2-oxazolylene provided herein. In anotherembodiment, Y is a triazolylene provided herein. In another embodiment,Y is a pyridinylene provided herein. In another embodiment, Y is apyrimidinylene provided herein.

In one embodiment, X is an isoxazolylene provided herein, and Y is apyrazolylene provided herein. In another embodiment, Y is animidazolylene provided herein. In another embodiment, Y is a1,2-thiazolylene provided herein. In another embodiment, Y is a1,3-thiazolylene provided herein. In another embodiment, Y is a1,2-oxazolylene provided herein. In another embodiment, Y is atriazolylene provided herein. In another embodiment, Y is a pyridinyleneprovided herein. In another embodiment, Y is a pyrimidinylene providedherein.

In one embodiment, X is an isothiazolylene provided herein, and Y is apyrazolylene provided herein. In another embodiment, Y is animidazolylene provided herein. In another embodiment, Y is a1,2-thiazolylene provided herein. In another embodiment, Y is a1,3-thiazolylene provided herein. In another embodiment, Y is a1,2-oxazolylene provided herein. In another embodiment, Y is atriazolylene provided herein. In another embodiment, Y is a pyridinyleneprovided herein. In another embodiment, Y is a pyrimidinylene providedherein.

In one embodiment, X is an imidazolylene provided herein, and Y is apyrazolylene provided herein. In another embodiment, Y is animidazolylene provided herein. In another embodiment, Y is a1,2-thiazolylene provided herein. In another embodiment, Y is a1,3-thiazolylene provided herein. In another embodiment, Y is a1,2-oxazolylene provided herein. In another embodiment, Y is atriazolylene provided herein. In another embodiment, Y is a pyridinyleneprovided herein. In another embodiment, Y is a pyrimidinylene providedherein.

In one embodiment, X is a triazolylene provided herein, and Y is apyrazolylene provided herein. In another embodiment, Y is animidazolylene provided herein. In another embodiment, Y is a1,2-thiazolylene provided herein. In another embodiment, Y is a1,3-thiazolylene provided herein. In another embodiment, Y is a1,2-oxazolylene provided herein. In another embodiment, Y is atriazolylene provided herein. In another embodiment, Y is a pyridinyleneprovided herein. In another embodiment, Y is a pyrimidinylene providedherein.

In some embodiments, Q is CH. In other embodiments, Q is N.

In some embodiments, Z is CR₅. In particular embodiments, R₅ is H. Inparticular embodiments, R₅ is F. In other embodiments, Z is N.

In some embodiments, R₄ is H. In other embodiments, R₄ is F.

In some embodiments, the compound of Formula (I) has the structure(I-A):

In other embodiments, the compound of Formula (I) has the structure(I-B):

In one embodiment, the compound is a compound of any one of thefollowing formulas, or an enantiomer, a mixture of enantiomers, or atautomer thereof, or a pharmaceutically acceptable salt thereof:

In certain embodiments, R₂ is each independently selected from the groupconsisting of H, CN, methyl, ethyl, isopropyl, chloro, methoxy,trifluoromethyl, 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, cyclopropylmethyl, cyclobutyl, and oxetanyl.

In certain embodiments, R₃ is selected from the group consisting of H,fluoro, chloro, bromo, CN, methoxy, difluoromethyl, trifluoromethyl,methyl, and ethyl.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

In certain embodiments the compound is selected from the groupconsisting of:

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of:

In certain embodiments the compound is selected from the groupconsisting of

In certain embodiments the compound is selected from the groupconsisting of:

In certain embodiments the compound is selected from the groupconsisting of

In certain embodiments the compound is selected from the groupconsisting of:

In certain embodiments the compound is selected from the groupconsisting of

In certain embodiments the compound is selected from the groupconsisting of

In certain embodiments the compound is selected from the groupconsisting of:

In certain embodiments the compound is selected from the groupconsisting of:

In certain embodiments the compound is selected from the groupconsisting of:

In certain embodiments the compound is selected from the groupconsisting of

In certain embodiments the compound is selected from the groupconsisting of

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments the compound is selected from the groupconsisting of

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In certain embodiments, the compound is selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a compound in Table 1:

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

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181or a pharmaceutically acceptable salt thereof.

For any compound in Table 1 that has a chiral center due to the presenceof non-hydrogen R₁, the R-enantiomer, the S-enantiomer, and the racemiccompound of such compound are all specifically provided herein, even ifnot specifically shown in Table 1.

In one embodiment, provided herein is a pharmaceutically acceptable saltof a compound of Formula (I). In one embodiment, provided herein is apharmaceutically acceptable salt of any compound in Table 1.

In certain embodiments, the pharmaceutically acceptable salt of thecompound is selected from the group consisting of alkyl ammonium salts,dialkyl ammonium salts, trialkyl ammonium salts, tetra-alkyl ammoniumsalts, L-arginine salts, benenthamine salts, benzathine salts, betainesalts, calcium hydroxide salts, choline salts, deanol salts,diethanolamine salts, diethylamine salts, 2-(diethylamino)ethanol salts,ethanolamine salts, ethylenediamine salts, N-methylglucamine salts,hydrabamine salts, 1H-imidazole salts, lithium salts, L-lysine salts,magnesium salts, 4-(2-hydroxyethyl)morpholine salts, piperazine salts,potassium salts, 1-(2-hydroxyethyl)pyrrolidine salts, sodium salts,triethanolamine salts, tromethamine salts, Na salts, Ca salts, K salts,Mg salts, and Zn salts.

In specific embodiments, the pharmaceutically acceptable salt is asolvate selected from the group consisting of water, methanol, ethanol,and dimethylformamide.

In certain embodiments the compound is a pharmaceutical compositionincluding a pharmaceutically acceptable carrier or excipient.

In specific embodiments, the composition is in a form selected from thegroup consisting of a tablet, a capsule, a granule, a lyophile forreconstitution, a powder, a solution, a syrup, a suppository, aninjection, a transdermal delivery system, and a solution suitable fortopical administration.

Methods of Use

Provided herein are methods of treating cancer comprising administeringa compound of the disclosure, such as a compound of Formula (I), or anenantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

Cancer is a disease of uncontrolled cell proliferation that results fromalterations in certain genes. Some of these alterations occur in genesthat encode receptor tyrosine kinases (RTKs), a family of membrane-boundproteins that transmit signals from outside the cell to promote cellsurvival, growth, and proliferation. Aberrant RTK activation can lead toexcessive cell growth and hence cancer. Generally, RTKs contain anN-terminal domain that binds extracellular ligands, a transmembranedomain, and a C-terminal kinase domain that catalyzes intracellularsignal transduction.

In some embodiments, the compound of Formula (1) is an inhibitor ofhuman ROS1. ROS1 is an RTK encoded by the ROS1 gene. The ligands andbiological functions of human ROS1 are unknown, but its homologs in someother species have been shown to bind extracellular ligands andstimulate cell differentiation. For example, mouse ROS1 is essential formale gamete maturation and reproduction. In humans, ROS1 chromosomalrearrangements are a well-documented cause of cancer, representing 1-2of non-small cell lung cancer (NSCLC) and a subset of many othercancers. These rearrangements result in the fusion of the C-terminus ofROS1 with the N-terminus of various partner proteins, the most common ofwhich is CD74. ROS1 fusions have constitutive kinase activity thatdrives tumor growth through MAPK, PI3K, and JAK/STAT signaling pathways.Small-molecule tyrosine kinase inhibitors (TKIs) have been used totarget ROS1 fusions in cancer, including crizotinib and entrectinib.Crizotinib was the first FDA-approved TKI for the treatment ofROS1-positive NSCLC, with an overall response rate of 60-80% and medianprogression-free survival of 9-19 months. Despite an initial response,most patients acquire resistance to crizotinib and relapse. Thepredominant mechanism of resistance is the G2032R mutation in thesolvent front, which dramatically reduces crizotinib affinity. Noinhibitors with activity against ROS1-G2032R fusions have beenFDA-approved, indicating a need in the art.

In some embodiments, the compound of Formula (I) is an inhibitor ofhuman anaplastic lymphoma kinase (ALK). ALK, also known as cluster ofdifferentiation 246 (CD246), is an RTK encoded by the ALK gene. ALK andROS1 are evolutionarily related; both belong to the insulin receptorsuperfamily, and their kinase domains share around 80% sequencesimilarity. A few ALK ligands in humans have been identified, includingpleiotrophin and midkine growth factors. While the roles of ALK inhumans remain inconclusive, much evidence from mouse studies suggeststhat it is important for the development of the nervous system. LikeROS1, ALK chromosomal rearrangements also lead to constitutively activefusion proteins that promote oncogenic transformation through MAPK,JAK/STAT, or other signaling pathways. ALK rearrangements represent 3-5of NSCLC, roughly half of anaplastic large-cell lymphoma (ALCL), and asubset of many other cancers, with the predominant fusions beingEML4-ALK for NSCLC and NPM1-ALK for ALCL. Oncogenic point mutations andamplification of ALK have also been observed, albeit at a much lowerfrequency than translocations. Crizotinib, ceritinib, alectinib,brigatinib, and lorlatinib are FDA-approved TKIs for the treatment ofALK-positive NSCLC and other cancers, either in front-line or afterprior therapy. Crizotinib, for example, shows an overall response rateof 60-80% and median progression-free survival of 8-11 months, which iscomparable to its activity in ROS1-positive NSCLC. Despite an initialresponse, many resistance mutations have emerged to the aforementionedFDA-approved TKIs. Some of these mutations, such as the combined L1196Mgatekeeper and G1202R solvent front mutation, are resistant to all ofthe approved drugs. New treatments of ALK-positive cancer harboringresistance mutations are a need in the art.

In further embodiments, the compound of Formula (I) is an inhibitor ofhuman tropomyosin receptor kinases (TRKs). The TRK family comprisesreceptor tyrosine kinases TRKA, TRKB, and TRKC, which are encoded by theNTRK1, NTRK2, and NTRK3 genes, respectively. Each TRK is activated by adifferent but overlapping set of neurotrophin ligands such as NGF, BDNF,and NT-3. All TRKs modulate similar downstream signaling pathways,consistent with sequence divergence in the ligand-binding domain butconvergence in the kinase domain (90% similarity). TRKs play crucialroles in the nervous system of developing and adult mammals byregulating processes such as memory, movement, pain, and proprioception.Like ROS1 and ALK, NTRK rearrangements lead to constitutively active TRKfusions that drive oncogenic transformation through MAPK, PI3K, andother pathways. TRK fusions are found in many cancers and represent over80% of the cases in secretory breast carcinoma, mammary analoguesecretory carcinomas, infantile fibrosarcoma, and congenital mesoblasticnephroma. Thus, inhibition of TRKs is advantageous for treating cancersexpressing TRK fusions.

Many ROS1 and ALK inhibitors in the prior art also exhibit potentinhibition of native non-oncogenic TRKs. This is a substantial drawbackbecause native TRKs play important functions in the nervous system, andinadvertent inhibition of native TRKs is associated with adversereactions including dizziness, ataxia, gait disturbance, paraesthesia,weight gain, and cognitive changes. New therapies that spare TRKs whileselectively targeting ROS1 and/or ALK, in their non-mutant and/or mutantforms, are a need in the art.

In one embodiment, provided herein is a method of decreasing a level ofROS1 or ALK in a cell, comprising contacting the cell with a compound ora pharmaceutical composition or a pharmaceutical combination providedherein. In an embodiment, such contact occurs in a cell in a mammal suchas a human. In an embodiment, such contact occurs in a cell in humanpatient having a cancer provided herein.

In one embodiment, a compound provided herein selectively inhibits ROS1.In one embodiment, the compound selectively inhibits ROS1 over ALK. Byway of non-limiting example, the ratio of selectivity can be greaterthan a factor of about 1.5, greater than a factor of about 2, greaterthan a factor of about 3, greater than a factor of about 4, greater thana factor of about 5, greater than a factor of about 10, greater than afactor of about 20, greater than a factor of about 30, greater than afactor of about 50, or greater than a factor of about 100, whereselectivity can be measured by ratio of IC₅₀ values, among other means.In one embodiment, the selectivity of ROS1 over ALK is measured by theratio of the IC₅₀ value against ALK to the IC₅₀ value against ROS1.

In one embodiment, the compound selectively inhibits ROS1 over TRK(e.g., TRKA, TRKB, and/or TRBC). By way of non-limiting example, theratio of selectivity can be greater than a factor of about 5, greaterthan a factor of about 10, greater than a factor of about 50, greaterthan a factor of about 100, greater than a factor of about 200, greaterthan a factor of about 400, greater than a factor of about 600, greaterthan a factor of about 800, greater than a factor of about 1000, greaterthan a factor of about 1500, greater than a factor of about 2000,greater than a factor of about 5000, greater than a factor of about10,000, or greater than a factor of about 20,000, where selectivity canbe measured by ratio of IC₅₀ values, among other means. In oneembodiment, the selectivity of ROS1 over TRK is measured by the ratio ofthe IC₅₀ value against TRK to the IC₅₀ value against ROS1.

In one embodiment, a compound provided herein selectively inhibits ALK.In one embodiment, the compound selectively inhibits ALK over ROS1. Byway of non-limiting example, the ratio of selectivity can be greaterthan a factor of about 1.5, greater than a factor of about 2, than afactor of about 3, greater than a factor of about 4, greater than afactor of about 5, or greater than a factor of about 10, whereselectivity can be measured by ratio of IC₅₀ values, among other means.In one embodiment, the selectivity of ALK over ROS1 is measured by theratio of the IC₅₀ value against ROS1 to the IC₅₀ value against ALK.

In one embodiment, the compound selectively inhibits ALK over TRK (e.g.,TRKA, TRKB, and/or TRBC). By way of non-limiting example, the ratio ofselectivity can be greater than a factor of about 5, greater than afactor of about 10, greater than a factor of about 50, greater than afactor of about 100, greater than a factor of about 200, greater than afactor of about 400, greater than a factor of about 600, greater than afactor of about 800, greater than a factor of about 1000, greater than afactor of about 1500, greater than a factor of about 2000, greater thana factor of about 5000, or greater than a factor of about 10,000, whereselectivity can be measured by ratio of IC₅₀ values, among other means.In one embodiment, the selectivity of ALK over TRK is measured by theratio of the IC₅₀ value against TRK to the IC₅₀ value against ALK.

In one embodiment, the compound selectively inhibits ROS1 and ALK overTRK (e.g., TRKA, TRKB, and/or TRBC). By way of non-limiting example, theratio of selectivity can be greater than a factor of about 5, greaterthan a factor of about 10, greater than a factor of about 50, greaterthan a factor of about 100, greater than a factor of about 200, greaterthan a factor of about 400, greater than a factor of about 600, greaterthan a factor of about 800, greater than a factor of about 1000, greaterthan a factor of about 1500, greater than a factor of about 2000,greater than a factor of about 5000, greater than a factor of about10,000, or greater than a factor of about 20,000, where selectivity canbe measured by ratio of IC₅₀ values, among other means. In oneembodiment, the selectivity of ROS1 and ALK over TRK is measured by theratio of the IC₅₀ value against TRK to the IC₅₀ value against ROS1 andALK.

In one embodiment, provided herein is a method for selectivelyinhibiting ROS1 over ALK wherein the inhibition takes place in a cell.In one embodiment, provided herein is a method for selectivelyinhibiting ROS1 over TRK (e.g., TRKA, TRKB, and/or TRBC) wherein theinhibition takes place in a cell. In one embodiment, the methodcomprises contacting ROS1 with an effective amount of a compoundprovided herein. In an embodiment, such contact occurs in a cell. In anembodiment, such contact occurs in a cell in a mammal such as a human.In an embodiment, such contact occurs in a cell in human patient havinga cancer provided herein.

In one embodiment, provided herein is a method for selectivelyinhibiting ROS1 over ALK wherein the inhibition takes place in a subjectsuffering from cancer, said method comprising administering an effectiveamount of a compound or a pharmaceutical composition provided herein tosaid subject. In certain embodiments, provided herein is a method oftreating a subject suffering from a cancer associated with ROS1, saidmethod comprising selectively inhibiting ROS1 over ALK by administeringan amount of a compound or a pharmaceutical composition provided hereinto said subject, wherein said amount is sufficient for selectiveinhibiting ROS1 over ALK.

In one embodiment, provided herein is a method for selectivelyinhibiting ROS1 over TRK (e.g., TRKA, TRKB, and/or TRBC) wherein theinhibition takes place in a subject suffering from cancer, said methodcomprising administering an effective amount of a compound or apharmaceutical composition provided herein to said subject. In certainembodiments, provided herein is a method of treating a subject sufferingfrom a cancer associated with ROS1, said method comprising selectivelyinhibiting ROS1 over TRK (e.g., TRKA, TRKB, and/or TRBC) byadministering an amount of a compound or a pharmaceutical compositionprovided herein to said subject, wherein said amount is sufficient forselective inhibiting ROS1 over TRK (e.g., TRKA, TRKB, and/or TRBC).

In one embodiment, provided herein is a method for selectivelyinhibiting ALK over ROS1 wherein the inhibition takes place in a cell.In one embodiment, provided herein is a method for selectivelyinhibiting ALK over TRK (e.g., TRKA, TRKB, and/or TRBC) wherein theinhibition takes place in a cell. In one embodiment, the methodcomprises contacting ALK with an effective amount of a compound providedherein. In an embodiment, such contact occurs in a cell. In anembodiment, such contact occurs in a cell in a mammal such as a human.In an embodiment, such contact occurs in a cell in human patient havinga cancer provided herein.

In one embodiment, provided herein is a method for selectivelyinhibiting ALK over ROS1 wherein the inhibition takes place in a subjectsuffering from cancer, said method comprising administering an effectiveamount of a compound or a pharmaceutical composition provided herein tosaid subject. In certain embodiments, provided herein is a method oftreating a subject suffering from a cancer associated with ALK, saidmethod comprising selectively inhibiting ALK over ROS1 by administeringan amount of a compound or a pharmaceutical composition provided hereinto said subject, wherein said amount is sufficient for selectiveinhibiting ALK over ROS1.

In one embodiment, provided herein is a method for selectivelyinhibiting ALK over TRK (e.g., TRKA, TRKB, and/or TRBC) wherein theinhibition takes place in a subject suffering from cancer, said methodcomprising administering an effective amount of a compound or apharmaceutical composition provided herein to said subject. In certainembodiments, provided herein is a method of treating a subject sufferingfrom a cancer associated with ALK, said method comprising selectivelyinhibiting ALK over TRK (e.g., TRKA, TRKB, and/or TRBC) by administeringan amount of a compound or a pharmaceutical composition provided hereinto said subject, wherein said amount is sufficient for selectiveinhibiting ALK over TRK (e.g., TRKA, TRKB, and/or TRBC).

As used herein and unless otherwise specified, inhibition of ROS1includes inhibition of wild type ROS1, or a mutation thereof, inhibitionof ALK includes inhibition of wild type ALK, or a mutation thereof, andinhibition of TRK includes inhibition of wild type TRK, or a mutationthereof.

Cancers treated by methods of the present disclosure include, but arenot limited to, lung cancer, e.g., non-small cell lung cancer,inflammatory myofibroblastic tumor, ovarian cancer, e.g., serous ovariancarcinoma, melanoma, e.g., spitzoid melanoma, glioblastoma, bile ductcancer, e.g., cholangiocarcinoma, gastric cancer, colorectal cancer,angiosarcoma, anaplastic large cell lymphoma, diffuse large B-celllymphoma, large B-cell lymphoma, esophageal cancer, e.g., esophagealsquamous cell carcinoma, kidney cancer, e.g., renal medullary carcinomaor renal cell carcinoma, breast cancer, e.g., triple negative breastcancer, thyroid cancer, e.g., papillary thyroid cancer, neuroblastoma,epithelioid hemangioendothelioma, colon cancer, and spitzoid tumor.

Cancers treated by methods of the present disclosure include cancersoriginating from one or more oncogenic proteins selected from ROS1, ALK,TRKA, TRKB, and TRKC. In certain embodiments, cancers treated by methodsof the present disclosure include cancers that are drug resistant totreatments directed at one or more oncogenic proteins selected fromROS1, ALK, TRKA, TRKB, and TRKC.

In one embodiment, the cancer in a method provided herein is anaplasticlymphoma kinase positive (ALK+). As used herein and unless otherwisespecified, an “ALK positive” (ALK+) cancer, disease, or disorder refersto a cancer, disease, or disorder characterized by inappropriately highexpression of an ALK gene and/or the presence of a mutation in an ALKgene. In one embodiment, the mutation alters the biological activity ofan ALK nucleic acid molecule or polypeptide. As used herein and unlessotherwise specified, a “mutation” or “mutant” of ALK comprises one ormore deletions, substitutions, insertions, inversions, duplications,translocations, or amplifications in the amino acid or nucleotidesequences of ALK, or fragments thereof. As used herein and unlessotherwise specified, an ALK “rearrangement” refers to genetictranslocations involving the ALK gene that may result in ALK fusiongenes and/or ALK fusion proteins. The ALK fusion can also include one ormore deletions, substitutions, insertions, inversions, duplications,translocations, or amplifications or a fragment thereof, as long as themutant retains kinase phosphorylation activity.

In one embodiment, the ALK mutation comprises one or more ALK pointmutations. In some embodiments, cancers treated by methods of thepresent disclosure include one or more mutations in ALK kinase. In oneembodiment, the one or more ALK point mutations are selected from pointmutations at L1152, C1156, I1171, F1174, V1180, L1196, L1198, G1202,D1203, S1206, E1210, F1245, G1269, and R1275. In one embodiment, the oneor more ALK point mutations are selected from G1202R, G1202K, L1196M,G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K,1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q,L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V. In one embodiment,the ALK mutation is G1202R. In one embodiment, the ALK mutation isL1196M. In one embodiment, the ALK mutation is G1269A. In oneembodiment, the ALK mutation is L1198F. In one embodiment, the ALKmutation is co-mutation of G1202R and one or more mutations selectedfrom L1196M, G1269A, and L1198F. In one embodiment, the ALK mutation isG1202R/L1196M dual mutation. In one embodiment, the ALK mutation isG1202R/G1269A dual mutation. In one embodiment, the ALK mutation isG1202R/L1198F dual mutation.

In one embodiment, the ALK mutation comprises one or more ALKrearrangements (in one embodiment, one rearrangement). In oneembodiment, the ALK mutation comprises one or more ALK fusions (in oneembodiment, one fusion). In some embodiments, cancers treated by methodsof the present disclosure include ALK fusions. In one embodiment, theALK fusion is with one of the fusion partners selected from EML4, TMP1,WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1,VCL, STRN, HIP1, NPM1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATICand KIFSB. In one embodiment, the ALK mutation is EML4-ALK, a fusionbetween the echinoderm microtubule-associated protein-like 4 (EML4) geneand the ALK tyrosine kinase domain. There are many variants of EML4-ALKthat differ by breakpoint junctions, with variant 1 (vi) and variant 3(v3) being the most prevalent clinically.

In one embodiment, the ALK mutation comprises one ALK rearrangement andone or more ALK point mutations. In one embodiment, the ALK mutation isEML4-ALK wt (variant 1). In one embodiment, the ALK mutation is EML4-ALKG1202R (variant 1). In one embodiment, the ALK mutation is EML4-ALKL1196M/G1202R (variant 1). In one embodiment, the ALK mutation isEML4-ALK G1202R/G1269A (variant 1). In one embodiment, the ALK mutationis EML4-ALK G1202R/L1198F (variant 1).

In one embodiment, the ALK+ cancer is determined by an FDA-approved testor other tests known in the art. The tests that can be used include,e.g., FoundationOne CDx™ (F1CDx) (a sequencing based in vitro diagnosticdevice for detection of substitutions, insertion and deletionalterations (indels), and copy number alterations (CNAs) in 324 genesand select gene rearrangements, as well as genomic signatures includingmicrosatellite instability (MSI) and tumor mutational burden (TMB) usingDNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissuespecimens); VENTANA ALK (D5F3) CDx Assay (qualitative detection of theanaplastic lymphoma kinase (ALK) protein in formalin-fixed,paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) tissuestained with the BenchMark XT or BenchMark ULTRA automated staininginstrument); and Vysis ALK Break Apart FISH Probe Kit test (aqualitative test to detect rearrangements involving the ALK gene viafluorescence in situ hybridization (FISH) in formalin-fixed,paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissuespecimens). In one embodiment, the test is a fluorescence in situhybridization (FISH) test, e.g., Vysis ALK Break Apart FISH Probe Kittest. Additional information for FDA-approved tests can be found at,e.g.,https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm303030.htm;and additional information for Vysis ALK Break Apart FISH Probe Kit canbe found at, e.g.,https://www.molecular.abbott/us/en/products/oncology/vysis-alk-break-apart-fish-probe-kit;the entirety of which are incorporated herein by reference.

Also provided are methods of treating a subject having a cancer (e.g., aALK positive cancer) that include: determining whether a cancer cell ina sample obtained from a subject having a cancer and previouslyadministered a first ALK inhibitor, has one or more ALK inhibitorresistance mutations; and administering a compound of Formula (I) or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin combination with another anticancer agent to the subject if thesubject has a cancer cell that has one or more ALK inhibitor resistancemutations. In some embodiments, the one or more ALK inhibitor resistancemutations confer increased resistance to a cancer cell or tumor totreatment with the first ALK inhibitor. In some embodiments, the one ormore ALK inhibitor resistance mutations include one or more ALKinhibitor resistance mutations. For example, the one or more ALKinhibitor resistance mutations can include a substitution at one or moreof amino acid positions 1202, 1196, 1269, 1156, 1171, 1174, 1180, 1206,1210, 1151, 1174, 1203, 1206, 1152, 1196, 1198, 1275, 1152, 1156, and1245, e.g., G1202R, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S,F1174L, V1180L, S1206Y, E1210K, 1151 Tins, F1174C, G1202del, D1203N,S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T,and F1245V. In some embodiments, another anticancer agent is anyanticancer agent known in the art. For example, another anticancer agentcan be another ALK inhibitor (e.g., a second ALK inhibitor).

In one embodiment, the cancer in a method provided herein is ROS1positive (ROS1+). As used herein and unless otherwise specified, a “ROS1positive” (ROS1+) cancer, disease, or disorder refers to a cancer,disease, or disorder characterized by inappropriately high expression ofa ROS1 gene and/or the presence of a mutation in a ROS1 gene. In oneembodiment, the mutation alters the biological activity of a ROS1nucleic acid molecule or polypeptide. As used herein and unlessotherwise specified, a “mutation” or “mutant” of ROS1 comprises one ormore deletions, substitutions, insertions, inversions, duplications,translocations, or amplifications in the amino acid or nucleotidesequences of ROS1, or fragments thereof. As used herein and unlessotherwise specified, a ROS1 “rearrangement” refers to genetictranslocations involving the ROS1 gene that may result in ROS1 fusiongenes and/or ROS1 fusion proteins. The ROS1 fusion can also include oneor more deletions, substitutions, insertions, inversions, duplications,translocations, or amplifications or a fragment thereof, as long as themutant retains kinase phosphorylation activity.

In one embodiment, the ROS1 mutation comprises one or more ROS1 pointmutations. In some embodiments, cancers treated by methods of thepresent disclosure include one or more mutations in ROS1 kinase. In oneembodiment, the one or more ROS1 point mutations are selected from pointmutations at E1935, L1947, L1951, G1971, E1974, L1982, 51986, F2004,E2020, L2026, G2032, D2033, C2060, F2075, L2086, V2089, V2098, G2101,D2113, and L2155. In one embodiment, the one or more ROS1 pointmutations are selected from G2032R, G2032K, D2033N, S1986F, S1986Y,L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V,E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S,and L2086F. In one embodiment, the ROS1 mutation is G2032R. In oneembodiment, the ROS1 mutation is S1986F. In one embodiment, the ROS1mutation is S1986Y. In one embodiment, the ROS1 mutation is L2026M. Inone embodiment, the ROS1 mutation is D2033N. In one embodiment, the ROS1mutation is L2086F. In one embodiment, the ROS1 mutation is F2004C. Inone embodiment, the ROS1 mutation is F2004V. In one embodiment, the ROS1mutation is G2101A. In one embodiment, the ROS1 mutation is L1982F. Inone embodiment, the ROS1 mutation is co-mutation of G2032R and one ormore of S1986F, S1986Y, F2004C, F2004V, L2026M, or D2033N.

In one embodiment, the ROS1 mutation comprises one or more ROS1rearrangements (in one embodiment, one rearrangement). In oneembodiment, the ROS1 mutation comprises one or more ROS1 fusions (in oneembodiment, one fusion). In some embodiments, cancers treated by methodsof the present disclosure include ROS1 fusions. In one embodiment, theROS1 fusion is with one of the fusion partners selected from SLC34A2,CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC (e.g.,GOPC-S, GOPC-L), GPRC6A, LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17 SLMAP,SRSF6, TFG, TMEM106B, TPD52L1, ZCCHC8, CCDC6, CAPRIN1, CEP85L, CHCHD3,CLIP1, EEF1G, KIF21A, KLC1, SART3, ST13, TRIM24, ERC1, FIP1L1, HLAA,KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2,APOB, PLG, RBP4, and GOLGB1. In one embodiment, the ROS1 fusion isCD74-ROS1 fusion. In one embodiment, the ROS1 fusion is SDC4-ROS1fusion. In one embodiment, the ROS1 fusion is EZR-ROS1 fusion. In oneembodiment, the ROS1 fusion is SLC34A2-ROS1 fusion. In one embodiment,the ROS1 fusion is GOPC-ROS1 fusion (e.g., GOPC-ROS1-S, GOPC-ROS1-L). Inone embodiment, the ROS1 fusion is CEP85L-ROS1 fusion.

In one embodiment, the ROS1 mutation comprises one ROS1 rearrangementsand one or more ROS1 point mutations. In one embodiment, the ROS1mutation comprises one or more ROS1 rearrangements from CD74-ROS1,EZR-ROS1, SLC34A2-ROS1, GOPC-ROS1 (e.g., GOPC-ROS1-S, GOPC-ROS1-L), andCEP85L-ROS1, and one or more ROS1 point mutations selected from F2004C,F2004V, and G2032R. In one embodiment, the ROS1 mutation comprises oneor more ROS1 rearrangements from CD74-ROS1, EZR-ROS1, and SLC34A2-ROS1,and ROS1 point mutation of G2101A.

In one embodiment, the ROS1 mutation is CD74-ROS1 F2004C. In oneembodiment, the ROS1 mutation is CD74-ROS1 F2004V. In one embodiment,the ROS1 mutation is CD74-ROS1 G2101A. In one embodiment, the ROS1mutation is CD74-ROS1 G2032R. In one embodiment, the ROS1 mutation isCD74-ROS1 S1986F. In one embodiment, the ROS1 mutation is CD74-ROS1L2026M. In one embodiment, the ROS1 mutation is CD74-ROS1 D2033N. In oneembodiment, the ROS1 mutation is EZR-ROS1 F2004C. In one embodiment, theROS1 mutation is EZR-ROS1 F2004V. In one embodiment, the ROS1 mutationis EZR-ROS1 G2101 A. In one embodiment, the ROS1 mutation is EZR-ROS1G2032R. In one embodiment, the ROS1 mutation is SLC34A2-ROS1 F2004C. Inone embodiment, the ROS1 mutation is SLC34A2-ROS1 F2004V. In oneembodiment, the ROS1 mutation is SLC34A2-ROS1 G2101A. In one embodiment,the ROS1 mutation is SLC34A2-ROS1 G2032R. In one embodiment, the ROS1mutation is GOPC-ROS1 F2004C (e.g., GOPC-ROS1-S F2004C, GOPC-ROS1-LF2004C). In one embodiment, the ROS1 mutation is GOPC-ROS1 F2004V (e.g.,GOPC-ROS1-S F2004V, GOPC-ROS1-L F2004V). In one embodiment, the ROS1mutation is GOPC-ROS1 G2032R (e.g., GOPC-ROS1-S G2032R, GOPC-ROS1-LG2032R). In one embodiment, the ROS1 mutation is CEP85L-ROS1 F2004C. Inone embodiment, the ROS1 mutation is CEP85L-ROS1 F2004V. In oneembodiment, the ROS1 mutation is CEP85L-ROS1 G2032R. In one embodiment,the ROS1 mutation is GOPC-ROS1 L1982F (e.g., GOPC-ROS1-S L1982F,GOPC-ROS1-L L1982F). In one embodiment, the ROS1 mutation is CD74-ROS1L1982F.

In one embodiment, the ROS1+ cancer is determined by an FDA-approvedtest or other tests known in the art. The tests that can be usedinclude, e.g., Oncomine™ Dx Target Test by Thermo Fisher Scientific. (aqualitative in vitro diagnostic test that uses targeted high-throughput,parallel-sequencing technology to detect sequence variations in 23 genesin DNA and RNA isolated from formalin-fixed, paraffin-embedded tumor(FFPE) tissue samples from patients with non-small cell lung cancer(NSCLC) using the Ion PGM Dx System); Vysis ROS1 Break Apart FISH ProbeKit (a qualitative test to detect rearrangements involving ROS1 generearrangements at 6q22 via fluorescence in situ hybridization (FISH) informalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer(NSCLC) tissue specimens) or RTReal Time-Polymerase Chain Reaction(RT-PCR) or NGSNext Generation Sequencing via a local diagnostic test.

Also provided are methods of treating a subject having a cancer (e.g., aROS1 positive cancer) that include: determining whether a cancer cell ina sample obtained from a subject having a cancer and previouslyadministered a first ROS1 inhibitor, has one or more ROS1 inhibitorresistance mutations; and administering a compound of Formula (I) or apharmaceutically acceptable salt or solvate thereof as a monotherapy orin conjunction with another anticancer agent to the subject if thesubject has a cancer cell that has one or more ROS1 inhibitor resistancemutations. In some embodiments, the one or more ROS1 inhibitorresistance mutations confer increased resistance to a cancer cell ortumor to treatment with the first ROS1 inhibitor. In some embodiments,the one or more ROS1 inhibitor resistance mutations include one or moreROS1 inhibitor resistance mutations. For example, the one or more ROS1inhibitor resistance mutations can include a substitution at one or moreof amino acid positions 2032, 2033, 1986, 2026, 1951, 1935, 1947, 1971,1974, 1982, 2004, 2020, 2060, 2075, 2089, 2098, 2101, 2113, 2155, 2032,and 2086, e.g., G2032R, D2033N, 51986F, 51986Y, L2026M, L1951R, E1935G,L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V,V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F. Insome embodiments, another anticancer agent is any anticancer agent knownin the art. For example, another anticancer agent can be another ROS1inhibitor (e.g., a second ROS1 inhibitor).

In one embodiment, a compound provided herein is a CNS-penetratingcompound. In one embodiment, after the administration of an effectiveamount of a compound provided herein (e.g., orally or intravenously),the compound is able to penetrate CNS (e.g., blood-brain barrier) andachieve a concentration in CNS (e.g., brain) that is still sufficient toinhibit (e.g., selectively inhibit) ROS1 or ALK or both.

In one embodiment, provided herein is a method for treating CNSmetastases of a cancer, comprising administering to a subject in needthereof an effective amount of a compound provided herein, e.g., acompound of Formula (I), or an enantiomer, a mixture of enantiomers, ora tautomer thereof, or a pharmaceutically acceptable salt thereof. Inone embodiment, the CNS metastases is brain metastases. In oneembodiment, the cancer is a ROS1+ cancer. In one embodiment, the canceris an ALK+ cancer.

In some embodiments, the compound is an inhibitor of human tropomyosinreceptor kinase A, B, or C. In certain embodiments, the IC₅₀ of thecompound for inhibition of mutant or non-mutant ROS1 or ALK is no morethan one-fifth of the IC₅₀ of the compound for inhibition of wild-typetropomyosin receptor kinase A, B, or C. TRK inhibition, particularly inthe central nervous system (CNS), has been associated with adversereactions, including dizziness/ataxia/gait disturbance, paraesthesia,weight gain and cognitive changes.

In some embodiments, provided is a method of minimizing adverse eventsin a subject in need of treatment for cancer (e.g., a ROS1 positivecancer or an ALK positive cancer), the method comprising administeringto the subject a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula (I), an enantiomer, a mixture ofenantiomers, or a tautomer thereof, or a pharmaceutically acceptablesalt thereof, and wherein the method minimizes adverse events associatedwith TRK inhibitors. In some embodiments, the cancer is aROS1-associated cancer or an ALK-associated (or ALK+) cancer. In someembodiments, the adverse events are TRK-related CNS adverse events.

As used herein “minimizing” adverse events refers to a reduction in theincidence of adverse events in a subject or patient population comparedto the paradigmatic incidence of adverse events in a subject or patientpopulation treated with TRK inhibitors (e.g., entrectinib,repotrectinib, or lorlatinib). In some embodiments, the incidence of anadverse event refers to the frequency or percentage of a specificadverse event over a subject or patient population. In some embodiments,the incidence of an adverse event refers to the total number of adverseevents experienced by an individual subject. In some embodiments,minimizing adverse events refers to minimizing TRK-related CNS adverseevents. In some embodiments, minimizing TRK-related CNS adverse eventsmeans less than 40 of the patient population has a TRK-related CNSadverse event. In some embodiments, minimizing TRK-related CNS adverseevents means less than 35%, less than 30%, less than 25%, less than 20%,less than 15%, less than 10 or less than 5% of the patient populationhas a TRK-related CNS adverse event. In some embodiments, minimizingTRK-related CNS adverse events means less than 12 of the patientpopulation have more than one TRK-related CNS adverse event. In someembodiments, minimizing TRK-related CNS adverse events means less than11%, less than 10%, less than 9%, less than 8%, less than 7%, less than6%, less than 5%, less than 4%, or less than 3 of the patient populationhave more than one TRK-related CNS adverse event.

In some embodiments, TRK-related CNS adverse events refers to one ormore of the following: dizziness, ataxia, gait disturbance,paraesthesia, weight gain, hyperphagia, paresthesias, abnormal movement,cognitive changes, speech effects (e.g, dysarthria, slow speech, orspeech disorder), mood disorder (e.g., irritability, anxiety,depression, affect lability, personality change, mood swings, affectivedisorder, aggression, agitation, mood altered, depressed mood, euphoricmood, or mania), and cognitive disorder (e.g., memory impairment,cognitive disorder, amnesia, confusion, disturbance in attention,delirium, mental impairment, attention deficit/hyperactivity disorder,dementia, or reading disorder).

In one embodiment, provided herein is a method for preventing orlimiting TRK-related CNS side effect or adverse event in a cancertreatment, comprising administering to a subject in need thereof aneffective amount of a compound provided herein, e.g., a compound ofFormula (I), or an enantiomer, a mixture of enantiomers, or a tautomerthereof, or a pharmaceutically acceptable salt thereof. In oneembodiment, the method prevents the occurance of the TRK-related CNSadverse event. In one embodiment, the method limits the frequency ofoccurance of the TRK-related CNS adverse event. In one embodiment, themethod limits the severity of the TRK-related side effect. In oneembodiment, provided herein is a method for treating CNS metastases of acancer with reduced TRK-related side effect, comprising administering toa subject in need thereof an effective amount of a compound providedherein, e.g., a compound of Formula (I), or an enantiomer, a mixture ofenantiomers, or a tautomer thereof, or a pharmaceutically acceptablesalt thereof. In one embodiment, the reduction/limiting/prevention inCNS side effect or adverse event is determined in a statistical sample,as compared to a standard of care treatment, e.g., an approved ROS1and/or ALK inhibitor (e.g., crizotinib, entrectinib, lorlatinib, orrepotrectinib) for ROS1+ and/or ALK+ cancer. In one embodiment, theTRK-related side effect is a TRKB-related CNS side effect. In oneembodiment, the TRK-related CNS side effect or adverse event isdizziness, ataxia, gait disturbance, paraesthesia, weight gain,cognitive impairment, a mood disorder, or sleep disturbance.

In one embodiment, provided herein is a method for treating cancer,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound provided herein, e.g., a compound ofFormula (I), or an enantiomer, a mixture of enantiomers, or a tautomerthereof, or a pharmaceutically acceptable salt thereof. In oneembodiment, the cancer is a ROS1-associated cancer. In one embodiment,the cancer is a ROS1+ cancer. In one embodiment, the cancer is anALK-associated cancer. In one embodiment, the cancer is an ALK+ cancer.In one embodiment, the cancer is identified to be ROS1+. In oneembodiment, the cancer is identified to be ALK+.

In one embodiment, provided herein is a method for treating a ROS1+cancer, comprising administering to a subject in need thereof atherapeutically effective amount of a compound provided herein, e.g., acompound of Formula (I), or an enantiomer, a mixture of enantiomers, ora tautomer thereof, or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method for treating an ALK+cancer, comprising administering to a subject in need thereof atherapeutically effective amount of a compound provided herein, e.g., acompound of Formula (I), or an enantiomer, a mixture of enantiomers, ora tautomer thereof, or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method for treating cancer in asubject, comprising: (i) identifying the cancer in the subject to beROS1+, and (ii) administering to the subject a therapeutically effectiveamount of a compound provided herein, e.g., a compound of Formula (I),or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method for treating cancer in asubject, comprising: (i) identifying the cancer in the subject to beALK+, and (ii) administering to the subject a therapeutically effectiveamount of a compound provided herein, e.g., a compound of Formula (I),or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is asolid tumor. In one embodiment, the cancer (or ROS1+ cancer, or ALK+cancer) is lung cancer, e.g., non-small cell lung cancer (NSCLC),glioblastoma, inflammatory myofibroblastic tumor (IMT), bile ductcancer, e.g., cholangiocarcinoma, ovarian cancer, e.g., serous ovariancarcinoma, gastric cancer, colorectal cancer, angiosarcoma, melanoma,e.g., spitzoid melanoma, epithelioid hemangioendothelioma, esophagealcancer, e.g., esophageal squamous cell carcinoma (ESCC), kidney cancer,e.g., renal medullary carcinoma or renal cell carcinoma, breast cancer,e.g., triple negative breast cancer, colon cancer, thyroid cancer, e.g.,papillary thyroid cancer, spitzoid tumor, or neuroblastoma.

In one embodiment, the cancer is lung cancer. In one embodiment, thecancer is non-small cell lung cancer. In one embodiment, the cancer isROS1+ non-small cell lung cancer. In one embodiment, the cancer is ALK+non-small cell lung cancer. In one embodiment, the cancer is relapsed orrefractory non-small cell lung cancer. In one embodiment, the cancer isrelapsed or refractory ROS1+ non-small cell lung cancer. In oneembodiment, the cancer is relapsed or refractory ALK+ non-small celllung cancer. In one embodiment, the cancer is newly diagnosed non-smallcell lung cancer. In one embodiment, the cancer is newly diagnosed ROS1+non-small cell lung cancer. In one embodiment, the cancer is newlydiagnosed ALK+ non-small cell lung cancer.

In one embodiment, the cancer is glioblastoma. In one embodiment, thecancer is ROS1+ glioblastoma. In one embodiment, the cancer is ALK+glioblastoma. In one embodiment, the cancer is relapsed or refractoryglioblastoma. In one embodiment, the cancer is relapsed or refractoryROS1+ glioblastoma. In one embodiment, the cancer is relapsed orrefractory ALK+ glioblastoma. In one embodiment, the cancer is newlydiagnosed glioblastoma. In one embodiment, the cancer is newly diagnosedROS1+ glioblastoma. In one embodiment, the cancer is newly diagnosedALK+ glioblastoma.

In one embodiment, the cancer is IMT. In one embodiment, the cancer isROS1+ IMT. In one embodiment, the cancer is ALK+ IMT. In one embodiment,the cancer is relapsed or refractory IMT. In one embodiment, the canceris relapsed or refractory ROS1+ IMT. In one embodiment, the cancer isrelapsed or refractory ALK+ IMT. In one embodiment, the cancer is newlydiagnosed IMT. In one embodiment, the cancer is newly diagnosed ROS1+IMT. In one embodiment, the cancer is newly diagnosed ALK+ IMT.

In one embodiment, the cancer is bile duct cancer. In one embodiment,the cancer is cholangiocarcinoma. In one embodiment, the cancer is ROS1+cholangiocarcinoma. In one embodiment, the cancer is ALK+cholangiocarcinoma. In one embodiment, the cancer is relapsed orrefractory cholangiocarcinoma. In one embodiment, the cancer is relapsedor refractory ROS1+ cholangiocarcinoma. In one embodiment, the cancer isrelapsed or refractory ALK+ cholangiocarcinoma. In one embodiment, thecancer is newly diagnosed cholangiocarcinoma. In one embodiment, thecancer is newly diagnosed ROS1+ cholangiocarcinoma. In one embodiment,the cancer is newly diagnosed ALK+ cholangiocarcinoma.

In one embodiment, the cancer is ovarian cancer. In one embodiment, thecancer is ROS1+ ovarian cancer. In one embodiment, the cancer is ALK+ovarian cancer. In one embodiment, the cancer is relapsed or refractoryovarian cancer. In one embodiment, the cancer is relapsed or refractoryROS1+ ovarian cancer. In one embodiment, the cancer is relapsed orrefractory ALK+ ovarian cancer. In one embodiment, the cancer is newlydiagnosed ovarian cancer. In one embodiment, the cancer is newlydiagnosed ROS1+ ovarian cancer. In one embodiment, the cancer is newlydiagnosed ALK+ ovarian cancer. In one embodiment, the ovarian cancer isserous ovarian carcinoma. In one embodiment, the ovarian cancer is highgrade serous ovarian carcinoma.

In one embodiment, the cancer is gastric cancer. In one embodiment, thecancer is ROS1+ gastric cancer. In one embodiment, the cancer is ALK+gastric cancer. In one embodiment, the cancer is relapsed or refractorygastric cancer. In one embodiment, the cancer is relapsed or refractoryROS1+ gastric cancer. In one embodiment, the cancer is relapsed orrefractory ALK+ gastric cancer. In one embodiment, the cancer is newlydiagnosed gastric cancer. In one embodiment, the cancer is newlydiagnosed ROS1+ gastric cancer. In one embodiment, the cancer is newlydiagnosed ALK+ gastric cancer.

In one embodiment, the cancer is colorectal cancer. In one embodiment,the cancer is ROS1+ colorectal cancer. In one embodiment, the cancer isALK+ colorectal cancer. In one embodiment, the cancer is relapsed orrefractory colorectal cancer. In one embodiment, the cancer is relapsedor refractory ROS1+ colorectal cancer. In one embodiment, the cancer isrelapsed or refractory ALK+ colorectal cancer. In one embodiment, thecancer is newly diagnosed colorectal cancer. In one embodiment, thecancer is newly diagnosed ROS1+ colorectal cancer. In one embodiment,the cancer is newly diagnosed ALK+ colorectal cancer.

In one embodiment, the cancer is angiosarcoma. In one embodiment, thecancer is ROS1+ angiosarcoma. In one embodiment, the cancer is ALK+angiosarcoma. In one embodiment, the cancer is relapsed or refractoryangiosarcoma. In one embodiment, the cancer is relapsed or refractoryROS1+ angiosarcoma. In one embodiment, the cancer is relapsed orrefractory ALK+ angiosarcoma. In one embodiment, the cancer is newlydiagnosed angiosarcoma. In one embodiment, the cancer is newly diagnosedROS1+ angiosarcoma. In one embodiment, the cancer is newly diagnosedALK+ angiosarcoma.

In one embodiment, the cancer is melanoma. In one embodiment, the canceris spitzoid tumor. In one embodiment, the cancer is spitzoid melanoma.In one embodiment, the cancer is ROS1+ spitzoid melanoma. In oneembodiment, the cancer is ALK+ spitzoid melanoma. In one embodiment, thecancer is relapsed or refractory spitzoid melanoma. In one embodiment,the cancer is relapsed or refractory ROS1+ spitzoid melanoma. In oneembodiment, the cancer is relapsed or refractory ALK+ spitzoid melanoma.In one embodiment, the cancer is newly diagnosed spitzoid melanoma. Inone embodiment, the cancer is newly diagnosed ROS1+ spitzoid melanoma.In one embodiment, the cancer is newly diagnosed ALK+ spitzoid melanoma.

In one embodiment, the cancer is epithelioid hemangioendothelioma. Inone embodiment, the cancer is ROS1+ epithelioid hemangioendothelioma. Inone embodiment, the cancer is ALK+ epithelioid hemangioendothelioma. Inone embodiment, the cancer is relapsed or refractory epithelioidhemangioendothelioma. In one embodiment, the cancer is relapsed orrefractory ROS1+ epithelioid hemangioendothelioma. In one embodiment,the cancer is relapsed or refractory ALK+ epithelioidhemangioendothelioma. In one embodiment, the cancer is newly diagnosedepithelioid hemangioendothelioma. In one embodiment, the cancer is newlydiagnosed ROS1+ epithelioid hemangioendothelioma. In one embodiment, thecancer is newly diagnosed ALK+ epithelioid hemangioendothelioma.

In one embodiment, the cancer is esophageal cancer. In one embodiment,the cancer is ESCC. In one embodiment, the cancer is ROS1+ ESCC. In oneembodiment, the cancer is ALK+ ESCC. In one embodiment, the cancer isrelapsed or refractory ESCC. In one embodiment, the cancer is relapsedor refractory ROS1+ ESCC. In one embodiment, the cancer is relapsed orrefractory ALK+ ESCC. In one embodiment, the cancer is newly diagnosedESCC. In one embodiment, the cancer is newly diagnosed ROS1+ ESCC. Inone embodiment, the cancer is newly diagnosed ALK+ ESCC.

In one embodiment, the cancer is kidney cancer. In one embodiment, thecancer is renal medullary carcinoma. In one embodiment, the cancer isROS1+ renal medullary carcinoma. In one embodiment, the cancer is ALK+renal medullary carcinoma. In one embodiment, the cancer is relapsed orrefractory renal medullary carcinoma. In one embodiment, the cancer isrelapsed or refractory ROS1+ renal medullary carcinoma. In oneembodiment, the cancer is relapsed or refractory ALK+ renal medullarycarcinoma. In one embodiment, the cancer is newly diagnosed renalmedullary carcinoma. In one embodiment, the cancer is newly diagnosedROS1+ renal medullary carcinoma. In one embodiment, the cancer is newlydiagnosed ALK+ renal medullary carcinoma. In one embodiment, the canceris renal cell carcinoma. In one embodiment, the cancer is ROS1+ renalcell carcinoma. In one embodiment, the cancer is ALK+ renal cellcarcinoma. In one embodiment, the cancer is relapsed or refractory renalcell carcinoma. In one embodiment, the cancer is relapsed or refractoryROS1+ renal cell carcinoma. In one embodiment, the cancer is relapsed orrefractory ALK+ renal cell carcinoma. In one embodiment, the cancer isnewly diagnosed renal cell carcinoma. In one embodiment, the cancer isnewly diagnosed ROS1+ renal cell carcinoma. In one embodiment, thecancer is newly diagnosed ALK+ renal cell carcinoma.

In one embodiment, the cancer is breast cancer. In one embodiment, thecancer is ROS1+ breast cancer. In one embodiment, the cancer is ALK+breast cancer. In one embodiment, the cancer is relapsed or refractorybreast cancer. In one embodiment, the cancer is relapsed or refractoryROS1+ breast cancer. In one embodiment, the cancer is relapsed orrefractory ALK+ breast cancer. In one embodiment, the cancer is newlydiagnosed breast cancer. In one embodiment, the cancer is newlydiagnosed ROS1+ breast cancer. In one embodiment, the cancer is newlydiagnosed ALK+ breast cancer. In one embodiment, the breast cancer istriple negative breast cancer.

In one embodiment, the cancer is colon cancer. In one embodiment, thecancer is ROS1+ colon cancer. In one embodiment, the cancer is ALK+colon cancer. In one embodiment, the cancer is relapsed or refractorycolon cancer. In one embodiment, the cancer is relapsed or refractoryROS1+ colon cancer. In one embodiment, the cancer is relapsed orrefractory ALK+ colon cancer. In one embodiment, the cancer is newlydiagnosed colon cancer. In one embodiment, the cancer is newly diagnosedROS1+ colon cancer. In one embodiment, the cancer is newly diagnosedALK+ colon cancer.

In one embodiment, the cancer is thyroid cancer. In one embodiment, thecancer is papillary thyroid cancer. In one embodiment, the cancer isROS1+ papillary thyroid cancer. In one embodiment, the cancer is ALK+papillary thyroid cancer. In one embodiment, the cancer is relapsed orrefractory papillary thyroid cancer. In one embodiment, the cancer isrelapsed or refractory ROS1+ papillary thyroid cancer. In oneembodiment, the cancer is relapsed or refractory ALK+ papillary thyroidcancer. In one embodiment, the cancer is newly diagnosed papillarythyroid cancer. In one embodiment, the cancer is newly diagnosed ROS1+papillary thyroid cancer. In one embodiment, the cancer is newlydiagnosed ALK+ papillary thyroid cancer.

In one embodiment, the cancer is neuroblastoma. In one embodiment, thecancer is ROS1+ neuroblastoma. In one embodiment, the cancer is ALK+neuroblastoma. In one embodiment, the cancer is relapsed or refractoryneuroblastoma. In one embodiment, the cancer is relapsed or refractoryROS1+ neuroblastoma. In one embodiment, the cancer is relapsed orrefractory ALK+ neuroblastoma. In one embodiment, the cancer is newlydiagnosed neuroblastoma. In one embodiment, the cancer is newlydiagnosed ROS1+ neuroblastoma. In one embodiment, the cancer is newlydiagnosed ALK+ neuroblastoma.

In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is ahematological cancer. In one embodiment, the cancer (or ROS1+ cancer, orALK+ cancer) is lymphoma. In one embodiment, the lymphoma is non-Hodgkinlymphoma. In one embodiment, the lymphoma is anaplastic large celllymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-celllymphoma. In addition to hematological cancer, methods for treatingother blood disorder or hematologic malignancy that is ROS1+ or ALK+ arealso provided herein.

In one embodiment, the cancer is ALCL. In one embodiment, the cancer isROS1+ ALCL. In one embodiment, the cancer is ALK+ ALCL. In oneembodiment, the cancer is relapsed or refractory ALCL. In oneembodiment, the cancer is relapsed or refractory ROS1+ ALCL. In oneembodiment, the cancer is relapsed or refractory ALK+ ALCL. In oneembodiment, the cancer is newly diagnosed ALCL. In one embodiment, thecancer is newly diagnosed ROS1+ ALCL. In one embodiment, the cancer isnewly diagnosed ALK+ ALCL.

In one embodiment, the cancer is DLBCL. In one embodiment, the cancer isROS1+ DLBCL. In one embodiment, the cancer is ALK+ DLBCL. In oneembodiment, the cancer is relapsed or refractory DLBCL. In oneembodiment, the cancer is relapsed or refractory ROS1+ DLBCL. In oneembodiment, the cancer is relapsed or refractory ALK+ DLBCL. In oneembodiment, the cancer is newly diagnosed DLBCL. In one embodiment, thecancer is newly diagnosed ROS1+ DLBCL. In one embodiment, the cancer isnewly diagnosed ALK+ DLBCL.

In one embodiment, the cancer is large B-cell lymphoma. In oneembodiment, the cancer is ROS1+ large B-cell lymphoma. In oneembodiment, the cancer is ALK+ large B-cell lymphoma. In one embodiment,the cancer is relapsed or refractory large B-cell lymphoma. In oneembodiment, the cancer is relapsed or refractory ROS1+ large B-celllymphoma. In one embodiment, the cancer is relapsed or refractory ALK+large B-cell lymphoma. In one embodiment, the cancer is newly diagnosedlarge B-cell lymphoma. In one embodiment, the cancer is newly diagnosedROS1+ large B-cell lymphoma. In one embodiment, the cancer is newlydiagnosed ALK+ large B-cell lymphoma.

In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is newdiagnosed. In one embodiment, the cancer (or ROS1+ cancer, or ALK+cancer) is previously untreated.

In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) isrelapsed or refractory. In one embodiment, the cancer is relapsed. Inone embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) isrefractory.

In one embodiment, the subject is previously untreated. In oneembodiment, the subject is treatment naïve to tyrosine kinase inhibitor(TKI) therapy. In one embodiment, the subject has received one or moreprior lines of therapy. In one embodiment, the subject has received twoor more prior lines of therapy. In one embodiment, the subject hasdeveloped resistance to one or more of the prior line of therapy. In oneembodiment, the prior therapy comprises a tyrosine kinase inhibitor(TKI). In one embodiment, the prior therapy comprises one or more ofcrizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib,repotrectinib, cabozantinib, foretinib, taletrectinib, merestinib,masitinib, and ensartinib. In one embodiment, the prior therapycomprises one or more chemotherapies. In one embodiment, the one or morechemotherapies are in addition to the TKI therapy.

In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) isresistant to a tyrosine kinase inhibitor (TKI).

In one embodiment, the cancer is resistant lung cancer. In oneembodiment, the cancer is resistant non-small cell lung cancer. In oneembodiment, the cancer is non-small cell lung cancer resistant to a TKI.In one embodiment, the cancer is ROS1+ non-small cell lung cancerresistant to a TKI. In one embodiment, the cancer is ALK+ non-small celllung cancer resistant to a TKI.

In one embodiment, the cancer is lung cancer (e.g., NSCLC), and thecancer is relapsed after, or refractory to, prior treatment by a TKI.

In one embodiment, a compound provided herein is administered asfirst-line treatment. In one embodiment, a compound provided herein isadministered as second-line treatment. In one embodiment, a compoundprovided herein is administered as third or fourth-line treatment.

In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) ismetastatic. In one embodiment, the cancer has CNS metastases. In oneembodiment, the cancer has brain metastases. In one embodiment, thecancer is metastatic non-small cell lung cancer (NSCLC). In oneembodiment, the cancer is metastatic ROS1+ NSCLC. In one embodiment, thecancer is metastatic ALK+ NSCLC.

In one embodiment, provided herein is a method for treating a patientwith metastatic ALK+ non-small cell lung cancer (NSCLC), comprisingadministering to the patient a therapeutically effective amount of acompound provided herein, e.g., a compound of Formula (I), or anenantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method for treating a patientwith metastatic ROS1+ non-small cell lung cancer (NSCLC), comprisingadministering to the patient a therapeutically effective amount of acompound provided herein, e.g., a compound of Formula (I), or anenantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.

In one embodiment, the patient is an adult patient. In one embodiment,the patient is a pediatric patient.

In one embodiment, provided herein is a method for treating an adultpatient with metastatic ROS1+ NSCLC, comprising administering to thepatient a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula (I), or an enantiomer, a mixture ofenantiomers, or a tautomer thereof, or a pharmaceutically acceptablesalt thereof.

In one embodiment, provided herein is a method for treating an adultpatient with metastatic ROS1+ NSCLC, comprising administering to thepatient a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula (I), or an enantiomer, a mixture ofenantiomers, or a tautomer thereof, or a pharmaceutically acceptablesalt thereof, wherein the patient has progressed on or is intolerant ofat least 1 prior TKI therapy.

In one embodiment, provided herein is a method for treating an adultpatient with metastatic NSCLC that is ROS1+ with solvent front mutationG2032R, comprising administering to the patient a therapeuticallyeffective amount of a compound provided herein, e.g., a compound ofFormula (I), or an enantiomer, a mixture of enantiomers, or a tautomerthereof, or a pharmaceutically acceptable salt thereof, wherein thepatient has progressed on or is intolerant of at least 1 prior TKItherapy.

In one embodiment, provided herein is a method for treating aROS1-associated (or ROS1+) cancer in a subject in need thereof, whereinthe cancer has developed resistance to a tyrosine kinase inhibitor(TKI), the method comprising administering to the subject atherapeutically effective amount of a compound provided herein, e.g., acompound of Formula (I), or an enantiomer, a mixture of enantiomers, ora tautomer thereof, or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method for treating aROS1-associated (or ROS1+) cancer in a subject in need thereof, whereinthe cancer has developed resistance to a tyrosine kinase inhibitor(TKI), and wherein the cancer has been identified as having one or moreROS1 inhibitor resistance mutations, the method comprising administeringto the subject a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula (I), or an enantiomer, a mixture ofenantiomers, or a tautomer thereof, or a pharmaceutically acceptablesalt thereof. In one embodiment, the one or more ROS1 inhibitorresistance mutations comprise one or more amino acid substitutions at anamino acid position selected from 1986, 2004, 2026, 2032, and 2033.

In one embodiment, the one or more ROS1 inhibitor resistance mutationscomprise one or more amino acid substitutions selected from S1986F,S1986Y, F2004C, F2004V, L2026M, G2032R, D2033N, L2086F, and G2101A. Inone embodiment, the one or more ROS1 inhibitor resistance mutations isG2032R. In one embodiment, the one or more ROS1 inhibitor resistancemutations comprise G2032R and one or more of S1986F, S1986Y, F2004C,F2004V, L2026M, D2033N, or G2101A. In one embodiment, the ROS1 inhibitorresistance mutation is L2086F.

In one embodiment, provided herein is a method for treating aALK-associated (or ALK+) cancer in a subject in need thereof, whereinthe cancer has developed resistance to a tyrosine kinase inhibitor(TKI), the method comprising administering to the subject atherapeutically effective amount of a compound provided herein, e.g., acompound of Formula (I), or an enantiomer, a mixture of enantiomers, ora tautomer thereof, or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method for treating aALK-associated (or ALK+) cancer in a subject in need thereof, whereinthe cancer has developed resistance to a tyrosine kinase inhibitor(TKI), and wherein the cancer has been identified as having one or moreALK inhibitor resistance mutations, the method comprising administeringo the subject a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula (I), or an enantiomer, a mixture ofenantiomers, or a tautomer thereof, or a pharmaceutically acceptablesalt thereof. In one embodiment, the one or more ALK inhibitorresistance mutations comprise one or more amino acid substitutions at anamino acid position selected from 1196, 1198, 1202, and 1269. In oneembodiment, the one or more ALK inhibitor resistance mutations compriseone or more amino acid substitutions selected from L1196M, L1198F,G1202R, and G1269A. In one embodiment, the one or more ALK inhibitorresistance mutations is G1202R. In one embodiment, the one or more ALKinhibitor resistance mutations comprise G1202R and one or more ofL1196M, L1198F, and G1269A.

In one embodiment, provided herein is a method for treating an adultpatient with metastatic NSCLC that is ALK+ with mutation G1202R,comprising administering to the patient a therapeutically effectiveamount of a compound provided herein, e.g., a compound of Formula (I),or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof, wherein the patient hasprogressed on or is intolerant of at least 1 prior TKI therapy.

In one embodiment, provided herein is a method for treating aALK-associated (or ALK+) cancer in a subject in need thereof, whereinthe cancer has developed resistance to a tyrosine kinase inhibitor(TKI), the method comprising administering to the subject atherapeutically effective amount of a compound provided herein, e.g., acompound of Formula (I), or an enantiomer, a mixture of enantiomers, ora tautomer thereof, or a pharmaceutically acceptable salt thereof.

In one embodiment, the TKI is a ROS1 inhibitor. In one embodiment, theTKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib,ceritinib, alectinib, brigatinib, lorlatinib, entrectinib,repotrectinib, cabozantinib, foretinib, merestinib, taletrectinib,masitinib, or ensartinib. In one embodiment, the TKI is crizotinib. Inone embodiment, the TKI is entrectinib.

In certain embodiments, the subject has relapsed after first-linetreatment of the cancer. In other embodiments, the subject has relapsedafter second-line treatment of the cancer.

In one embodiment, the cancer or disease is in a pediatric patient(including an infantile patient). In one embodiment, the cancer issystemic anaplastic large cell lymphoma (ALCL) that is ALK+ in pediatricpatients 1 year of age or older, and young adults. In anotherembodiment, the cancer is relapsed or refractory systemic anaplasticlarge cell lymphoma (ALCL) that is ALK+ in pediatric patients 1 year ofage or older, and young adults. In one embodiment, the cancer issystemic anaplastic large cell lymphoma (ALCL) that is ROS1+ inpediatric patients 1 year of age or older, and young adults. In anotherembodiment, the cancer is relapsed or refractory systemic anaplasticlarge cell lymphoma (ALCL) that is ROS1+ in pediatric patients 1 year ofage or older, and young adults.

In certain embodiments, the methods for treating or preventing cancercan be demonstrated by one or more responses such as increasedapoptosis, inhibition of tumor growth, reduction of tumor metastasis,inhibition of tumor metastasis, reduction of microvessel density,decreased neovascularization, inhibition of tumor migration, tumorregression, and increased survival of the subject.

Combination Treatments

In some embodiments, the method of treating or preventing cancer maycomprise administering a compound of Formula (I) conjointly with one ormore other chemotherapeutic agent(s).

As used herein and unless otherwise specified, by “conjointly” or “incombination with”, it is not intended to imply that the other agent andthe compound of Formula (I) must be administered at the same time and/orformulated for delivery together, although these methods of delivery arewithin the scope of this disclosure. The compound provided herein can beadministered concurrently with, prior to (e.g., 5 minutes, 15 minutes,30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks,5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before), or subsequentto (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12weeks, or 16 weeks after), one or more other agents (e.g., one or moreother additional agents). In general, each therapeutic agent isadministered at a dose and/or on a time schedule determined for thatparticular agent. The other therapeutic agent can be administered withthe compound provided herein in a single composition or separately in adifferent composition. Triple therapy is also contemplated herein.

Chemotherapeutic agents that may be conjointly administered withcompounds of the disclosure include:1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate(acid blue 25),1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine,anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerinvaccine (bcg), bicalutamide, bleomycin, bortezomib, β-methylene-ADP(AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, campothecin,capecitabine, carboplatin, carfilzomib, carmustine, ceritinib,chlorambucil, chloroquine, cisplatin, cladribine, clodronate,cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone,cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin,dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol,docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol,estramustine, etoposide, everolimus, exemestane, filgrastim,fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide,gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea,idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone,lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine,lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan,mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin,mitotane, mitoxantrone, MK-2206, mutamycin,N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, nilutamide,nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate,pazopanib, pemexetred, pentostatin, perifosine, PF-04691502, plicamycin,pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed,ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin,rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate,sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen,temozolomide, temsirolimus, teniposide, testosterone, thalidomide,thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan,trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine,vindesine, vinorelbine, and vorinostat (SAHA). In other embodiments,chemotherapeutic agents that may be conjointly administered withcompounds of the disclosure include: ABT-263, dexamethasone,5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In otherembodiments, chemotherapeutic agents that may be conjointly administeredwith compounds of the disclosure include:1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate(acid blue 25),1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,APCP, $-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine,fludarabine, doxorubicin, gemcitabine,N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS,quercetin, reactive blue 2, rolofylline sodium2,4-dinitrobenzenesulfonate, sumarin, and tonapofylline.

Many combination therapies have been developed for the treatment ofcancer. In certain embodiments, compounds of the disclosure (e.g.,compounds of Formula (I)) may be conjointly administered with one ormore combination therapies. Examples of combination therapies with whichcompounds of the disclosure may be conjointly administered are includedin Table 2.

TABLE 2 Exemplary combinatorial therapies for the treatment of cancerName Therapeutic agents ABV Doxorubicin, Bleomycin, Vinblastine ABVDDoxorubicin, Bleomycin, Vinblastine, Dacarbazine AC (Breast)Doxorubicin, Cyclophosphamide AC (Sarcoma) Doxorubicin, Cisplatin AC(Neuroblastoma) Cyclophosphamide, Doxorubicin ACE Cyclophosphamide,Doxorubicin, Etoposide ACe Cyclophosphamide, Doxorubicin AD Doxorubicin,Dacarbazine AP Doxorubicin, Cisplatin ARAC-DNR Cytarabine, DaunorubicinB-CAVe Bleomycin, Lomustine, Doxorubicin, Vinblastine BCVPP Carmustine,Cyclophosphamide, Vinblastine, Procarbazine, Prednisone BEACOPPBleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine,Procarbazine, Prednisone, Filgrastim BEP Bleomycin, Etoposide, CisplatinBIP Bleomycin, Cisplatin, Ifosfamide, Mesna BOMP Bleomycin, Vincristine,Cisplatin, Mitomycin CA Cytarabine, Asparaginase CABO Cisplatin,Methotrexate, Bleomycin, Vincristine CAF Cyclophosphamide, Doxorubicin,Fluorouracil CAL-G Cyclophosphamide, Daunorubicin, Vincristine,Prednisone, Asparaginase CAMP Cyclophosphamide, Doxorubicin,Methotrexate, Procarbazine CAP Cyclophosphamide, Doxorubicin, CisplatinCAV Cyclophosphamide, Doxorubicin, Vincristine CAVE ADD CAV andEtoposide CA-VP16 Cyclophosphamide, Doxorubicin, Etoposide CCCyclophosphamide, Carboplatin CDDP/VP-16 Cisplatin, Etoposide CEFCyclophosphamide, Epirubicin, Fluorouracil CEPP(B) Cyclophosphamide,Etoposide, Prednisone, with or without/Bleomycin CEV Cyclophosphamide,Etoposide, Vincristine CF Cisplatin, Fluorouracil or CarboplatinFluorouracil CHAP Cyclophosphamide or Cyclophosphamide, Altretamine,Doxorubicin, Cisplatin ChlVPP Chlorambucil, Vinblastine, Procarbazine,Prednisone CHOP Cyclophosphamide, Doxorubicin, Vincristine, PrednisoneCHOP-BLEO Add Bleomycin to CHOP CISCA Cyclophosphamide, Doxorubicin,Cisplatin CLD-BOMP Bleomycin, Cisplatin, Vincristine, Mitomycin CMFMethotrexate, Fluorouracil, Cyclophosphamide CMFP Cyclophosphamide,Methotrexate, Fluorouracil, Prednisone CMFVP Cyclophosphamide,Methotrexate, Fluorouracil, Vincristine, Prednisone CMV Cisplatin,Methotrexate, Vinblastine CNF Cyclophosphamide, Mitoxantrone,Fluorouracil CNOP Cyclophosphamide, Mitoxantrone, Vincristine,Prednisone COB Cisplatin, Vincristine, Bleomycin CODE Cisplatin,Vincristine, Doxorubicin, Etoposide COMLA Cyclophosphamide, Vincristine,Methotrexate, Leucovorin, Cytarabine COMP Cyclophosphamide, Vincristine,Methotrexate, Prednisone Cooper Regimen Cyclophosphamide, Methotrexate,Fluorouracil, Vincristine, Prednisone COP Cyclophosphamide, Vincristine,Prednisone COPE Cyclophosphamide, Vincristine, Cisplatin, Etoposide COPPCyclophosphamide, Vincristine, Procarbazine, Prednisone CP(ChronicChlorambucil, Prednisone lymphocytic leukemia) CP (Ovarian Cancer)Cyclophosphamide, Cisplatin CVD Cisplatin, Vinblastine, Dacarbazine CVICarboplatin, Etoposide, Ifosfamide, Mesna CVP Cyclophosphamide,Vincristine, Prednisome CVPP Lomustine, Procarbazine, Prednisone CYVADICCyclophosphamide, Vincristine, Doxorubicin, Dacarbazine DA Daunorubicin,Cytarabine DAT Daunorubicin, Cytarabine, Thioguanine DAV Daunorubicin,Cytarabine, Etoposide DCT Daunorubicin, Cytarabine, Thioguanine DHAPCisplatin, Cytarabine, Dexamethasone DI Doxorubicin, IfosfamideDTIC/Tamoxifen Dacarbazine, Tamoxifen DVP Daunorubicin, Vincristine,Prednisone EAP Etoposide, Doxorubicin, Cisplatin EC Etoposide,Carboplatin EFP Etoposie, Fluorouracil, Cisplatin ELF Etoposide,Leucovorin, Fluorouracil EMA 86 Mitoxantrone, Etoposide, Cytarabine EPEtoposide, Cisplatin EVA Etoposide, Vinblastine FAC Fluorouracil,Doxorubicin, Cyclophosphamide FAM Fluorouracil, Doxorubicin, MitomycinFAMTX Methotrexate, Leucovorin, Doxorubicin FAP Fluorouracil,Doxorubicin, Cisplatin F-CL Fluorouracil, Leucovorin FEC Fluorouracil,Cyclophosphamide, Epirubicin FED Fluorouracil, Etoposide, Cisplatin FLFlutamide, Leuprolide FZ Flutamide, Goserelin acetate implant HDMTXMethotrexate, Leucovorin Hexa-CAF Altretamine, Cyclophosphamide,Methotrexate, Fluorouracil IDMTX/6-MP Methotrexate, Mercaptopurine,Leucovorin IE Ifosfamide, Etoposie, Mesna IfoVP Ifosfamide, Etoposide,Mesna IPA Ifosfamide, Cisplatin, Doxorubicin M-2 Vincristine,Carmustine, Cyclophosphamide, Prednisone, Melphalan MAC-IIIMethotrexate, Leucovorin, Dactinomycin, Cyclophosphamide MACCMethotrexate, Doxorubicin, Cyclophosphamide, Lomustine MACOP-BMethotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine,Bleomycin, Prednisone MAID Mesna, Doxorubicin, Ifosfamide, Dacarbazinem-BACOD Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine,Dexamethasone, Methotrexate, Leucovorin MBC Methotrexate, Bleomycin,Cisplatin MC Mitoxantrone, Cytarabine MF Methotrexate, Fluorouracil,Leucovorin MICE Ifosfamide, Carboplatin, Etoposide, Mesna MINE Mesna,Ifosfamide, Mitoxantrone, Etoposide mini-BEAM Carmustine, Etoposide,Cytarabine, Melphalan MOBP Bleomycin, Vincristine, Cisplatin, MitomycinMOP Mechlorethamine, Vincristine, Procarbazine MOPP Mechlorethamine,Vincristine, Procarbazine, Prednisone MOPP/ABV Mechlorethamine,Vincristine, Procarbazine, Prednisone, Doxorubicin, Bleomycin,Vinblastine MP (multiple Melphalan, Prednisone myeloma) MP (prostatecancer) Mitoxantrone, Prednisone MTX/6-MO Methotrexate, MercaptopurineMTX/6-MP/VP Methotrexate, Mercaptopurine, Vincristine, PrednisoneMTX-CDDPAdr Methotrexate, Leucovorin, Cisplatin, Doxorubicin MV (breastcancer) Mitomycin, Vinblastine MV (acute myelocytic Mitoxantrone,Etoposide leukemia) M-VAC Methotrexate Vinblastine, Doxorubicin,Cisplatin MVP Mitomycin Vinblastine, Cisplatin MVPP Mechlorethamine,Vinblastine, Procarbazine, Prednisone NFL Mitoxantrone, Fluorouracil,Leucovorin NOVP Mitoxantrone, Vinblastine, Vincristine OPA Vincristine,Prednisone, Doxorubicin OPPA Add Procarbazine to OPA. PAC Cisplatin,Doxorubicin PAC-I Cisplatin, Doxorubicin, Cyclophosphamide PA-CICisplatin, Doxorubicin PCV Lomustine, Procarbazine, Vincristine PFLCisplatin, Fluorouracil, Leucovorin POC Prednisone, Vincristine,Lomustine ProMACE Prednisone, Methotrexate, Leucovorin, Doxorubicin,Cyclophosphamide, Etoposide ProMACE/cytaBOM Prednisone, Doxorubicin,Cyclophosphamide, Etoposide, Cytarabine, Bleomycin, Vincristine,Methotrexate, Leucovorin, Cotrimoxazole PRoMACE/MOPP Prednisone,Doxorubicin, Cyclophosphamide, Etoposide, Mechlorethamine, Vincristine,Procarbazine, Methotrexate, Leucovorin Pt/VM Cisplatin, Teniposide PVAPrednisone, Vincristine, Asparaginase PVB Cisplatin, Vinblastine,Bleomycin PVDA Prednisone, Vincristine, Daunorubicin, Asparaginase SMFStreptozocin, Mitomycin, Fluorouracil TAD Mechlorethamine, Doxorubicin,Vinblastine, Vincristine, Bleomycin, Etoposide, Prednisone TTTMethotrexate, Cytarabine, Hydrocortisone Topo/CTX Cyclophosphamide,Topotecan, Mesna VAB-6 Cyclophosphamide, Dactinomycin, Vinblastine,Cisplatin, Bleomycin VAC Vincristine, Dactinomycin, CyclophosphamideVACAdr Vincristine, Cyclophosphamide, Doxorubicin, Dactinomycin,Vincristine VAD Vincristine, Doxorubicin, Dexamethasone VATHVinblastine, Doxorubicin, Thiotepa, Flouxymesterone VBAP Vincristine,Carmustine, Doxorubicin, Prednisone VBCMP Vincristine, Carmustine,Melphalan, Cyclophosphamide, Prednisone VC Vinorelbine, Cisplatin VCAPVincristine, Cyclophosphamide, Doxorubicin, Prednisone VD Vinorelbine,Doxorubicin VelP Vinblastine, Cisplatin, Ifosfamide, Mesna VIPEtoposide, Cisplatin, Ifosfamide, Mesna VM Mitomycin, Vinblastine VMCPVincristine, Melphalan, Cyclophosphamide, Prednisone VP Etoposide,Cisplatin V-TAD Etoposide, Thioguanine, Daunorubicin, Cytarabine 5 + 2Cytarabine, Daunorubicin, Mitoxantrone 7 + 3 Cytarabine with/,Daunorubicin or Idarubicin or Mitoxantrone “8 in 1” Methylprednisolone,Vincristine, Lomustine, Procarbazine, Hydroxyurea, Cisplatin,Cytarabine, Dacarbazine

In certain embodiments, the conjoint therapies of the disclosurecomprise conjoint administration with other types of chemotherapeuticagents, such as immuno-oncology agents. Cancer cells often have specificcell surface antigens that can be recognized by the immune system. Thus,immuno-oncology agents, such as monoclonal antibodies, can selectivelybind to cancer cell antigens and effect cell death. Otherimmuno-oncology agents can suppress tumor-mediated inhibition of thenative immune response or otherwise activate the immune response andthus facilitate recognition of the tumor by the immune system. Exemplaryantibody immuno-oncology agents, include, but are not limited to,abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox,apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, and tremelimumab. Insome embodiments, the antibody immuno-oncology agents are selected fromanti-CD73 monoclonal antibody (mAb), anti-CD39 mAb, anti-PD-1 mAb, andanti-CTLA4 mAb. Thus, in some embodiments, the methods of the disclosurecomprise conjoint administration of one or more immuno-oncology agents,such as the agents mentioned above.

In some embodiments, the combination therapy comprises conjointadministration of a compound of the disclosure, such as a compound ofFormula (I), with SH2 inhibitors, such as CGP78850, CPG85793, C90, C126,G7-18NATE, G7-B1, and NSC642056.

In some embodiments, the combination therapy comprises conjointadministration of a compound of the disclosure, such as a compound ofFormula (I), with MEK inhibitors, such as trametinib, cobimetinib,binimetinib, selumetinib, PD-325901, CI-1040, and TAK-733.

In some embodiments, the combination therapy comprises conjointadministration of a compound of the disclosure, such as a compound ofFormula (I), with a MET inhibitor selected from JNJ-38877605,PF-04217903, foretinib, AMG 458, tivantinib, cabozantinib, crizotinib,capmatinib hydrochloride, tepotinib hydrochloride, and savolitinib.

In some embodiments, the combination therapy comprises conjointadministration of a compound of the discloser, such as Formula (I), witha SHP2 inhibitor selected from TNO-155, RMC-4630, JAB-3068, or RLY-1971.

In some embodiments, the combination therapy comprises conjointadministration of a compound of the disclosure, such as a compound ofFormula (I), with a RAS inhibitor selected from aliskiren, captopril,losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan,azilsartan, telmisartan, eprosartan, benazepril, enalapril, lisinopril,perindopril, quinapril, ramipril, and trandolapril.

In some embodiment, the combination therapy comprises administration ofa compound provided herein, e.g., a compound of Formula (I), incombination with a TKI.

In one embodiment, the TKI is a ROS1 inhibitor. In one embodiment, theTKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib,ceritinib, alectinib, brigatinib, lorlatinib, entrectinib,repotrectinib, cabozantinib, foretinib, merestinib, taletrectinib,masitinib, or ensartinib. In one embodiment, the TKI is crizotinib. Inone embodiment, the TKI is entrectinib. In one embodiment, the TKI isalectinib. In one embodiment, the TKI is brigatinib.

In some embodiments, the combination therapy comprises conjointadministration of a compound of the disclosure, such as a compound ofFormula (I), with anti-PD-1 therapy. In certain embodiments, thecombination therapy comprises conjoint administration of a compound ofthe disclosure, such as a compound of Formula (I), with oxaliplatin. Inother embodiments, the combination therapy comprises conjointadministration of a compound of the disclosure, such as a compound ofFormula (I), with doxorubicin.

In certain embodiments, a compound of the disclosure may be conjointlyadministered with non-chemical methods of cancer treatment. In certainembodiments, a compound of the disclosure may be conjointly administeredwith radiation therapy. In certain embodiments, a compound of thedisclosure may be conjointly administered with surgery, withthermoablation, with focused ultrasound therapy, with cryotherapy, orwith any combination of these.

In certain embodiments, compounds of the disclosure may be conjointlyadministered with one or more other compounds of the disclosure.Moreover, such combinations may be conjointly administered with othertherapeutic agents, such as other agents suitable for the treatment ofcancer, immunological or neurological diseases, such as the agentsidentified above. In certain embodiments, conjointly administering oneor more additional chemotherapeutic agents with a compound of thedisclosure provides a synergistic effect. In certain embodiments,conjointly administering one or more additional chemotherapeutic agentsprovides an additive effect.

Pharmaceutical Compositions

In certain embodiments, the present disclosure provides a pharmaceuticalpreparation suitable for use in a human patient, comprising any of thecompounds shown above (e.g., a compound of the disclosure, such as acompound of Formula (I), and one or more pharmaceutically acceptableexcipients. In certain embodiments, the pharmaceutical preparations maybe for use in treating or preventing a condition or disease as describedherein. Any of the disclosed compounds may be used in the manufacture ofmedicaments for the treatment of any diseases or conditions disclosedherein.

The compositions and methods of the present disclosure may be utilizedto treat a subject in need thereof. In certain embodiments, the subjectis a mammal such as a human, or a non-human mammal. When administered tosubject, such as a human, the composition or the compound is preferablyadministered as a pharmaceutical composition comprising, for example, acompound of the disclosure and a pharmaceutically acceptable carrier.Pharmaceutically acceptable carriers are well known in the art andinclude, for example, aqueous solutions such as water or physiologicallybuffered saline or other solvents or vehicles such as glycols, glycerol,oils such as olive oil, or injectable organic esters. In a preferredembodiment, when such pharmaceutical compositions are for humanadministration, particularly for invasive routes of administration(i.e., routes, such as injection or implantation, that circumventtransport or diffusion through an epithelial barrier), the aqueoussolution is pyrogen-free, or substantially pyrogen-free. The excipientscan be chosen, for example, to effect delayed release of an agent or toselectively target one or more cells, tissues or organs. Thepharmaceutical composition can be in dosage unit form such as tablet,capsule (including sprinkle capsule and gelatin capsule), granule,lyophile for reconstitution, powder, solution, syrup, suppository,injection or the like. The composition can also be present in atransdermal delivery system, e.g., a skin patch. The composition canalso be present in a solution suitable for topical administration, suchas an eye drop.

A pharmaceutically acceptable carrier can contain physiologicallyacceptable agents that act, for example, to stabilize, increasesolubility or to increase the absorption of a compound such as acompound of the disclosure. Such physiologically acceptable agentsinclude, for example, carbohydrates, such as glucose, sucrose ordextrans, antioxidants, such as ascorbic acid or glutathione, chelatingagents, low molecular weight proteins or other stabilizers orexcipients. The choice of a pharmaceutically acceptable carrier,including a physiologically acceptable agent, depends, for example, onthe route of administration of the composition. The preparation orpharmaceutical composition can be a self-emulsifying drug deliverysystem or a self-microemulsifying drug delivery system. Thepharmaceutical composition (preparation) also can be a liposome or otherpolymer matrix, which can have incorporated therein, for example, acompound of the disclosure. Liposomes, for example, which comprisephospholipids or other lipids, are nontoxic, physiologically acceptableand metabolizable carriers that are relatively simple to make andadminister.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the subject. Some examples of materials which can serve aspharmaceutically acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other nontoxic compatible substances employed in pharmaceuticalformulations.

A pharmaceutical composition (preparation) can be administered to asubject by any of a number of routes of administration including, forexample, orally (for example, drenches as in aqueous or non-aqueoussolutions or suspensions, tablets, capsules (including sprinkle capsulesand gelatin capsules), boluses, powders, granules, pastes forapplication to the tongue); absorption through the oral mucosa (e.g.,sublingually); anally, rectally or vaginally (for example, as a pessary,cream or foam); parenterally (including intramuscularly, intravenously,subcutaneously or intrathecally as, for example, a sterile solution orsuspension); nasally; intraperitoneally; subcutaneously; transdermally(for example as a patch applied to the skin); and topically (forexample, as a cream, ointment or spray applied to the skin, or as an eyedrop). The compound may also be formulated for inhalation. In certainembodiments, a compound may be simply dissolved or suspended in sterilewater. Details of appropriate routes of administration and compositionssuitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and4,172,896, as well as in patents cited therein.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thesubject being treated, the particular mode of administration. The amountof active ingredient that can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect. Generally, out of onehundred percent, this amount will range from about 1 percent to aboutninety-nine percent of active ingredient, preferably from about 5percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association an active compound, such as a compound ofthe disclosure, with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound of the presentdisclosure with liquid carriers, or finely divided solid carriers, orboth, and then, if necessary, shaping the product.

Formulations of the disclosure suitable for oral administration may bein the form of capsules (including sprinkle capsules and gelatincapsules), cachets, pills, tablets, lozenges (using a flavored basis,usually sucrose and acacia or tragacanth), lyophile, powders, granules,or as a solution or a suspension in an aqueous or non-aqueous liquid, oras an oil-in-water or water-in-oil liquid emulsion, or as an elixir orsyrup, or as pastilles (using an inert base, such as gelatin andglycerin, or sucrose and acacia) and/or as mouth washes and the like,each containing a predetermined amount of a compound of the presentdisclosure as an active ingredient. Compositions or compounds may alsobe administered as a bolus, electuary or paste.

To prepare solid dosage forms for oral administration (capsules(including sprinkle capsules and gelatin capsules), tablets, pills,dragees, powders, granules and the like), the active ingredient is mixedwith one or more pharmaceutically acceptable carriers, such as sodiumcitrate or dicalcium phosphate, and/or any of the following: (1) fillersor extenders, such as starches, lactose, sucrose, glucose, mannitol,and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, cetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; (10) complexing agents,such as, modified and unmodified cyclodextrins; and (11) coloringagents. In the case of capsules (including sprinkle capsules and gelatincapsules), tablets and pills, the pharmaceutical compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions, such as dragees, capsules (including sprinkle capsules andgelatin capsules), pills and granules, may optionally be scored orprepared with coatings and shells, such as enteric coatings and othercoatings well known in the pharmaceutical-formulating art. They may alsobe formulated so as to provide slow or controlled release of the activeingredient therein using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile, otherpolymer matrices, liposomes and/or microspheres. They may be sterilizedby, for example, filtration through a bacteria-retaining filter, or byincorporating sterilizing agents in the form of sterile solidcompositions that can be dissolved in sterile water, or some othersterile injectable medium immediately before use. These compositions mayalso optionally contain opacifying agents and may be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain portion of the gastrointestinal tract, optionally, in a delayedmanner. Examples of embedding compositions that can be used includepolymeric substances and waxes. The active ingredient can also be inmicroencapsulated form, if appropriate, with one or more of theabove-described excipients.

Liquid dosage forms useful for oral administration includepharmaceutically acceptable emulsions, lyophiles for reconstitution,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, cyclodextrins and derivatives thereof, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions for rectal, vaginal, orurethral administration may be presented as a suppository, which may beprepared by mixing one or more active compounds with one or moresuitable nonirritating excipients or carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the rectum or vaginal cavity and releasethe active compound.

Formulations of the pharmaceutical compositions for administration tothe mouth may be presented as a mouthwash, or an oral spray, or an oralointment.

Alternatively or additionally, compositions can be formulated fordelivery via a catheter, stent, wire, or other intraluminal device.Delivery via such devices may be especially useful for delivery to thebladder, urethra, ureter, rectum, or intestine.

Formulations which are suitable for vaginal administration also includepessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining such carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. The active compound may be mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound, excipients, such as animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present disclosure to the body. Suchdosage forms can be made by dissolving or dispersing the active compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this disclosure.Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Pat.No. 6,583,124, the contents of which are incorporated herein byreference. If desired, liquid ophthalmic formulations have propertiessimilar to that of lacrimal fluids, aqueous humor or vitreous humor orare compatible with such fluids. A preferred route of administration islocal administration (e.g., topical administration, such as eye drops,or administration via an implant).

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

Pharmaceutical compositions suitable for parenteral administrationcomprise one or more active compounds in combination with one or morepharmaceutically acceptable sterile isotonic aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the disclosure includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsulated matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

For use in the methods of this disclosure, active compounds can be givenper se or as a pharmaceutical composition containing, for example, 0.1to 99.5% (more preferably, 0.5 to 90%) of active ingredient incombination with a pharmaceutically acceptable carrier.

Methods of introduction may also be provided by rechargeable orbiodegradable devices. Various slow release polymeric devices have beendeveloped and tested in vivo in recent years for the controlled deliveryof drugs, including proteinacious biopharmaceuticals. A variety ofbiocompatible polymers (including hydrogels), including bothbiodegradable and non-degradable polymers, can be used to form animplant for the sustained release of a compound at a particular targetsite.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions may be varied so as to obtain an amount of the activeingredient that is effective to achieve the desired therapeutic responsefor a particular patient, composition, and mode of administration,without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound or combination ofcompounds employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound(s) being employed, the duration of the treatment,other drugs, compounds and/or materials used in combination with theparticular compound(s) employed, the age, sex, weight, condition,general health and prior medical history of the subject being treated,and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the therapeutically effective amount of thepharmaceutical composition required. For example, the physician orveterinarian could start doses of the pharmaceutical composition orcompound at levels lower than that required in order to achieve thedesired therapeutic effect and gradually increase the dosage until thedesired effect is achieved. By “therapeutically effective amount” ismeant the concentration of a compound that is sufficient to elicit thedesired therapeutic effect. It is generally understood that theeffective amount of the compound will vary according to the weight, sex,age, and medical history of the subject. Other factors which influencethe effective amount may include, but are not limited to, the severityof the subject's condition, the disorder being treated, the stability ofthe compound, and, if desired, another type of therapeutic agent beingadministered with the compound of the disclosure. A larger total dosecan be delivered by multiple administrations of the agent. Methods todetermine efficacy and dosage are known to those skilled in the art(Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13ed., 1814-1882, herein incorporated by reference).

In general, a suitable daily dose of an active compound used in thecompositions and methods of the disclosure will be that amount of thecompound that is the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above.

If desired, the effective daily dose of the active compound may beadministered as one, two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. In certain embodiments of the presentdisclosure, the active compound may be administered two or three timesdaily. In certain embodiments, the active compound will be administeredonce daily.

In certain embodiments, compounds of the disclosure may be used alone orconjointly administered with another type of therapeutic agent. As usedherein, the phrase “conjoint administration” refers to any form ofadministration of two or more different therapeutic compounds such thatthe second compound is administered while the previously administeredtherapeutic compound is still effective in the body (e.g., the twocompounds are simultaneously effective in the subject, which may includesynergistic effects of the two compounds). For example, the differenttherapeutic compounds can be administered either in the same formulationor in a separate formulation, either concomitantly or sequentially. Incertain embodiments, the different therapeutic compounds can beadministered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72hours, or a week of one another. Thus, a subject who receives suchtreatment can benefit from a combined effect of different therapeuticcompounds.

In certain embodiments, conjoint administration of compounds of thedisclosure with one or more additional therapeutic agent(s) (e.g., oneor more additional chemotherapeutic agent(s)) provides improved efficacyrelative to each individual administration of the compound of thedisclosure (e.g., compound of Formula I or Ia) or the one or moreadditional therapeutic agent(s). In certain such embodiments, theconjoint administration provides an additive effect, wherein an additiveeffect refers to the sum of each of the effects of individualadministration of the compound of the disclosure and the one or moreadditional therapeutic agent(s).

This disclosure includes the use of pharmaceutically acceptable salts ofcompounds of the disclosure in the compositions and methods of thepresent disclosure. In certain embodiments, contemplated salts of thedisclosure include, but are not limited to, alkyl, dialkyl, trialkyl ortetra-alkyl ammonium salts. In certain embodiments, contemplated saltsof the disclosure include, but are not limited to, L-arginine,benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol,diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine,ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium,L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine,potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine,tromethamine, and zinc salts. In certain embodiments, contemplated saltsof the disclosure include, but are not limited to, Na, Ca, K, Mg, Zn orother metal salts.

The pharmaceutically acceptable acid addition salts can also exist asvarious solvates, such as with water, methanol, ethanol,dimethylformamide, and the like. Mixtures of such solvates can also beprepared. The source of such solvate can be from the solvent ofcrystallization, inherent in the solvent of preparation orcrystallization, or adventitious to such solvent.

Pharmaceutically acceptable anionic salts include acetate, aspartate,benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide,camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate,fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate,hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate,maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate,octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate,propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate,teoclate, and tosylate.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1)water-soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfiteand the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, alpha-tocopherol, and the like; and (3)metal-chelating agents, such as citric acid, ethylenediamine tetraaceticacid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The disclosure now being generally described, it will be more readilyunderstood by reference to the following examples which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present disclosure, and are not intended to limit the disclosure.

General Synthetic Procedures

The starting materials and reagents used in preparing these compoundsare either available from commercial supplier such as Aldrich ChemicalCo., Bachem, etc., or can be made by methods well known in the art. Theschemes are merely illustrative of some methods by which the compoundsdisclosed herein can be synthesized and various modifications to theseschemes can be made and will be suggested to one of skill in the arthaving referred to this disclosure. The starting materials and theintermediates and the final products of the reaction may be isolated andpurified if desired using congenital techniques, including but notlimited to filtration, distillation, crystallization, chromatography,and the like and may be characterized using conventional means,including physical constants and spectral data. In some instances,reactions may produce more than one regioisomeric product. In thesecases, chromatography may be used to separate the isomers and NOE orNOESY INMR spectroscopy may be used to aid structural assignment.

Unless specified otherwise, the reactions described herein take place atatmospheric pressure over a temperature range from about −78° C. toabout 150° C.

Abbreviations Definition Solvents EA, EtOAc ethyl acetate PE, pet. etherpetroleum ether THF tetrahydrofuran DCM dichloromethane DMFN,N-dimethylformamide DMA N,N-dimethylacetamide NMPN-methyl-2-pyrrolidone DMSO dimethyl sulfoxide IPA isopropyl alcohol DMEdimethoxyethane MeCN, ACN acetonitrile DCE dichloroethane Reagents DASTdiethylaminosulfur trifluoride DIAD diisopropyl azodicarboxylate DEADdiethyl azodicarboxylate DBAD di-tert-butyl azodicarboxylate DIPEA, DIEAN,N-diisopropylethylamine TEA triethylamine ATP adenosine triphosphateTFA trifluoroacetic acid FA formic acid DIBAL, DIBAL-H,diisobutylaluminium hydride DIBALH AcOH, HOAc acetic acid TEStriethylsilane n-BuLi, BuLi n-butyllithium LDA lithium diisopropylamideNBS N-bromosuccinimide NIS N-iodosuccinimide NCS N-chlorosuccinimide DMPDess-Martin periodinane DEA diethylamine DMF-DMA1,1-dimethoxy-N,N-dimethylmethanamine TMP 2,2,6,6-tetramethylpiperidineNMO N-methylmorpholine N-oxide TBSCl tert-butyldimethylsilyl chlorideKOAc, AcOK potassium acetate NaOAc, AcONa sodium acetate SEMCl2-(trimethylsilyl)ethoxymethyl chloride tBuLi, t-BuLi tert-butyllithiumNFSI N-fluorobenzenesulfonimide AIBN azobisisobutyronitrile EDCI1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HOBT hydroxybenzotriazoleTBAF tetra-n-butylammonium fluoride HATU1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl cataCXium A di(1-adamantyl)-n-butylphosphine DPPP1,3-bis(diphenylphosphino)propane DPPF1,1′-bis(diphenylphosphino)ferrocene TfOH triflic acid HMTA1,3,5,7-tetraazaadamantane PMBCl p-methoxybenzyl chloride HEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid EGTA ethyleneglycol-bis(2-aminoethylether)-N,N,N′,N′- tetraacetic acid Other HPLChigh-pressure liquid chromatography Prep preparative wt wild-type rt,r.t., RT room-temperature SFC supercritical fluid chromatography V/Vvolume/volume LC/MS, LC-MS, liquid chromatography-mass spectrometry LCMSMS mass spectrometry ESI, ES+, ES− electrospray ionization NMR nuclearmagnetic resonance ppm parts per million sat saturated aq aqueous TLCthin layer chromatography t_(R) retention time

The compounds of the invention can be prepared by a variety of syntheticmethods, as further described and illustrated herein. It will beunderstood by those with skill in the art that the following generalsynthetic methods are representative and not intended to be limiting.Racemic compounds can be enantiomerically enriched via chiral,preparative, SFC or HPLC separation. Variable A denotes a carbon,nitrogen or sulfur atom that can be the same or different as anotherinstance of variable A. Variable X denotes a chloride, bromide or iodideatom that can be the same or different as another instance of variableX. Variable Z denotes a nitrogen atom, or C—H or C—F group that can bethe same or different as another instance of variable Z.

Poly-halide I may be coupled with stannane II using Stille couplingconditions to provide compounds of type III. Various additives including(but not limited to) LiCl or CuI may be optionally employed tofacilitate this reaction. Intramolecular ring closure of poly-halide IIImay be effected using two-step, one-pot borylation/Suzuki cross-couplingconditions to afford compounds of type IV.

Halide V may be coupled with stannane IT using Stille couplingconditions to provide compounds of type VI. Various additives including(but not limited to) LiCl or CuI may be optionally employed tofacilitate this reaction. Intramolecular ring closure of halide VI maybe effected using C—H insertion cross-coupling conditions to affordcompounds of type IV. Potassium acetate or potassium pivalate areeffective bases for the macrocyclization step.

Nitropyridine VII may be reduced using Fe metal conditions to provideaminopyridines of type VIII. In cases where the substrate contains anisoxazole moiety, yields can be improved by using SnCl₂ conditionsinstead. Intramolecular ring closure of VIII may be effected usingtwo-step, one-pot borylation/Suzuki cross-coupling conditions to affordcompounds of type IX.

Nitropyridine X may be reduced using Fe metal conditions to provideaminopyridines of type XI. In cases where the substrate contains anisoxazole moiety, yields can be improved by using SnCl₂ conditionsinstead. Intramolecular ring closure of XI may be effected using C—Hinsertion cross-coupling conditions to afford compounds of type IX.Potassium acetate or potassium pivalate are effective bases for themacrocyclization step.

Alcohol XII may be reacted with chloropyrazine XIII using SNAr couplingconditions to form ether XIV. Intramolecular ring closure of XIV may beeffected using two-step, one-pot borylation/Suzuki cross-couplingconditions to afford compounds of type XV.

Alcohol XVI may be reacted with chloropyrazine XIII using SNAr couplingconditions to form ether XVII. Intramolecular ring closure of XVII maybe effected using C—H insertion cross-coupling conditions to affordcompounds of type XV. Potassium acetate or potassium pivalate areeffective bases for the macrocyclization step.

Aminopyridine XVIII may be brominated with a suitable brominatingreagent to provide bromide XIX. Desilylation of XIX using a suitablefluoride ion source, followed by intramolecular ring closure usingtwo-step, one-pot borylation/Suzuki cross-coupling conditions may affordcompounds of type XX.

Nitropyridine XXI may be reduced using Fe metal conditions to provideaminopyridines of type XXII. In cases where the substrate contains anisoxazole moiety, yields can be improved by using SnCl₂ conditionsinstead. Intramolecular ring closure of XXII using C—H insertioncross-coupling conditions, followed by TBAF desilylation affordscompounds of type XX. Potassium acetate or potassium pivalate areeffective bases for the macrocyclization step.

Nitropyridine XXIII may be converted to compound XI by reduction usingFe metal conditions followed by bromination with a suitable brominatingreagent. Intramolecular ring closure of XI may be effected using C—Hinsertion cross-coupling conditions to afford compounds of type IX.Potassium acetate or potassium pivalate are effective bases for themacrocyclization step.

Compounds of type XXIV may be deprotected to provide compounds of typeIV by treatment with a suitable acid in solution (e.g. TFA or HCl).Protecting groups amenable to this method include, but are not limitedto, the methoxymethyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, and p-methoxybenzyl groups.

Nitropyridine XXV may be reduced using Fe metal conditions to provideaminopyridines of type XI. In cases where the substrate contains anisoxazole moiety, yields can be improved by using SnCl₂ conditionsinstead. Intramolecular ring closure of XI may be effected using C—Hinsertion cross-coupling conditions to afford compounds of type IX.Potassium acetate or potassium pivalate are effective bases for themacrocyclization step.

Nitropyridine X may be reduced using iron metal, and then brominatedwith NBS to provide aminopyridines of type XXVI. In cases where thesubstrate contains an isoxazole moiety, yields can be improved by usingSnCl₂ reducing conditions instead of iron. Intramolecular ring closureof XXVI may be effected using two-step, one-pot borylation/Suzukicross-coupling conditions to afford compounds of type IX.

Compounds of type XXVII may be first deprotected by hydrogenolysis usingpalladium on carbon under a hydrogen atmosphere, followed by alkylationof the resulting hydroxyl group with an alkyl halide (e.g. methyliodide) to provide compounds of type XXVIII. Protecting groups amenableto this method include, but are not limited to, the benzyl andp-methoxybenzyl groups.

Nitropyridine XXIX may be reduced using Fe metal conditions to provideaminopyridines of type XXX. In cases where the substrate contains anisoxazole moiety, yields can be improved by using SnCl₂ conditionsinstead. Intramolecular ring closure of XXX may be effected using C—Hinsertion cross-coupling conditions to afford ketones of type XXXI.Potassium acetate or potassium pivalate are effective bases for themacrocyclization step. Reduction of the ketone XXXI to the alcohols oftype XXXII can be effected using sodium borohydride. Finally,deoxygenation may be performed using triethylsilane and trifluoroaceticacid to afford compounds of type IX.

Those having skill in the art will recognize that the starting materialsand reaction conditions may be varied, the sequence of the reactionsaltered, and additional steps employed to produce compounds encompassedby the present disclosure, as demonstrated by the following examples. Insome cases, protection of certain reactive functionalities may benecessary to achieve some of the above transformations. In general, theneed for such protecting groups as well as the conditions necessary toattach and remove such groups will be apparent to experienced organicchemists. The disclosures of all articles and references mentioned inthis application, including patents, are incorporated herein byreference.

The preparation of the compounds of the present disclosure isillustrated further by the following examples, which are not to beconstrued as limiting the disclosure in scope or spirit to the specificprocedures and compounds described in them.

Analytical Methods

LCMS data was collected using one of the following methods:

LCMS Method Method Details A Instrument: Agilent1260-6125B Column: YMCTriart C18, 50 × 4.6 mm, 5 μm Mobile phase: A is H₂O (+0.05% FA) and Bis CH₃CN (+0.05% FA) Run Time: 20% B (0.1 min); 20-95% B (1.4 min); 95%B (0.7 min); 20% B (0.5 min) Flow rate: 2.5 mL/min Column temperature:35° C. Wavelength: 220 nm/254 nm B Instrument: SHIMADZU 2020 Column:Inertsustain C18, 50 × 4.6 mm, 5 μm Mobile phase: A is H₂O (+0.1% FA)and B is CH₃CN Run Time: 15% B (0.6 min); 15-95% B (3.2 min); 95% B (0.5min); 15% B (0.7 min) Flow rate: 2.5 mL/min Column temperature: 35° C.Wavelength: 220 nm/254 nm C Instrument: SHIMADZU 2020 Column: YMC-TriartC18, 50 × 4.6 mm, 5 μm Mobile phase: A is H₂O (+0.1% FA) and B is CH₃CNRun Time: 20% B (0.1 min); 20-95% B (1.7 min); 95% B (0.7 min); 20% B(0.4 min) Flow rate: 2.5 mL/min Column temperature: 35° C. Wavelength:220 nm/254 nm D Instrument: SHIMADZU 2020 Column: YMC-Triart C18, 50 ×4.6 mm, 5 μm Mobile phase: A is H₂O (+0.1% FA) and B is CH₃CN Run Time:0% B (0.6 min); 0-50% B (3.2 min); 50% B (0.5 min); 0% B (0.4 min) Flowrate: 2.5 mL/min Column temperature: 35° C. Wavelength: 220 nm/254 nm EInstrument: SHIMADZU 2020 Column: Inertsustain C18, 50 × 4.6 mm, 5 μmMobile phase: A is H₂O (+0.1% FA) and B is CH₃CN Run Time: 0% B (0.1min); 0-50% B (1.7 min); 50% B (0.7 min); 0% B (0.4 min) Flow rate: 2.5mL/min Column temperature: 35° C. Wavelength: 220 nm/254 nm FInstrument: SHIMADZU 2020 Column: Shim-pack GIST C18, 50 × 4.6 mm, 5 μmMobile phase: A is H₂O (+0.1% FA) and B is CH₃CN Run Time: 20% B (0.1min); 20-95% B (1.7 min); 95% B (0.7 min); 20% B (0.4 min) Flow rate:2.5 mL/min Column temperature: 35° C. Wavelength: 220 nm/254 nm GInstrument: SHIMADZU 2020 Column: Shim-pack GIST C18, 50 × 4.6 mm, 5 μmMobile phase: A is H₂O (+0.1% FA) and B is CH₃CN Run Time: 0% B (0.6min); 0-50% B (3.2 min); 50% B (0.5 min); 0% B (0.4 min) Flow rate: 2.5mL/min Column temperature: 35° C. Wavelength: 220 nm/254 nm HInstrument: SHIMADZU 2020 Column: Inertsil ODS-3 C18, 50 × 4.6 mm, 5 μmMobile phase: A is H₂O (+0.04% aq. NH₃) and B is CH₃CN Run Time: 20% B(0.1 min); 20-95% B (1.7 min); 95% B (0.7 min); 20% B (0.4 min) Flowrate: 2.5 mL/min Column temperature: 35° C. Wavelength: 220 nm/254 nm IInstrument: SHIMADZU 2010 Column: Shim-pack GIST C18, 50 × 4.6 mm, 5 μmMobile phase: A is 10% CH₃CN in H₂O + 0.05% FA and B is CH₃CN Run Time:20-95% B (1.8 min); 95% B (0.9 min) Flow rate: 2.3 mL/min Columntemperature: 40° C. Wavelength: 220 nm/254 nm J Instrument: SHIMADZU2020 Column: Inertsil ODS-3 C18, 50 × 4.6 mm, 5 μm Mobile phase: A isH₂O (+0.04% aq. NH₃) and B is CH₃CN Run Time: 15% B (0.6 min); 15-95% B(3.2 min); 95% B (0.5 min); 15% B (0.4 min) Flow rate: 2.5 mL/min Columntemperature: 35° C. Wavelength: 220 nm/254 nm K Instrument: SHIMADZU2020 Column: Kromasil Eternity XT C18, 50 × 4.6 mm, 5 μm Mobile phase: Ais H₂O (+0.1% FA) and B is CH₃CN Run Time: 20% B (0.1 min); 20-95% B(1.7 min); 95% B (0.7 min); 20% B (0.4 min) Flow rate: 2.5 mL/min Columntemperature: 35° C. Wavelength: 220 nm/254 nm L Instrument: SHIMADZU2020 Column: YMC Triart C18, 50 × 4.6 mm, 5 μm Mobile phase: A is H₂O(+0.1% FA) and B is CH₃CN Run Time: 15% B (0.6 min); 15-95% B (3.2 min);95% B (0.5 min); 15% B (0.4 min) Flow rate: 2.5 mL/min Columntemperature: 35° C. Wavelength: 220 nm/254 nm M Instrument: SHIMADZU2020 Column: Shim-pack GIST C18, 50 × 4.6 mm, 5 μm Mobile phase: A isH₂O (+0.05% FA) and B is CH₃CN Run Time: 0% B (0.6 min); 0-70% B (3.2min); 70% B (0.5 min); 0% B (0.4 min) Flow rate: 2.5 mL/min Columntemperature: 35° C. Wavelength: 220 nm/254 nm

Synthetic Examples Intermediates Synthesis of3-chloro-4-iodo-1H-pyrazole

To a stirred solution of 3-chloro-1H-pyrazole (25.00 g, 243.8 mmol) inDMF (250 mL) was added NIS (71.3 g, 317 mmol) portion-wise at 0° C. over30 min. After the addition, the mixture was stirred at 25° C. for 1 hand then concentrated by oil pump to remove DMF. The residue was dilutedwith EtOAc, washed with sat. NaHCO₃ (250 mL×2) and brine (250 mL×2),dried over Na₂SO₄ and concentrated to dryness to give crude3-chloro-4-iodo-1H-pyrazole (55.7 g, 96%) as a brown oil. LC/MS (ESI)m/z: 229 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

3-(benzyloxy)-5-bromo-1-ethyl-4-iodo-1H-pyrazole

m/z (ESI): 407 [M + H]

Synthesis of 1-methyl-3-vinyl-1H-pyrazole

To a mixture of 3-iodo-1-methyl-1H-pyrazole (14.00 g, 67.31 mmol) andpotassium vinyltrifluoroborate (27.06 g, 201.9 mmol) in 1,4-dioxane (200mL) and water (50 mL) were added K₂CO₃ (27.9 g, 202 mmol) andPd(dppf)Cl₂ (0.98 g, 1.4 mmol) at r.t. The mixture was degassed forthree times under N₂ atmosphere, and this mixture was stirred at 100° C.for 12 h. The mixture was filtered, and the filtrate was diluted withEtOAc (100 mL), washed with water (100 mL) and brine (100 mL), driedover anhydrous Na₂SO₄ and concentrated to dryness. The residue waspurified by column chromatography on silica gel (PE:EtOAc=20:1) to give1-methyl-3-vinyl-1H-pyrazole (4.25 g, 58% yield) as a yellow oil. LC/MS(ESI) (m/z): 109 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-ethyl-3-vinyl-1H-pyrazole

m/z (ESI): 123 [M + H]2-(2-ethenyl-4-fluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole

m/z (ESI): 319 [M + H] methyl 1-methyl-3-vinyl-1H-pyrazole-5-carboxylate

m/z (ESI): 167 [M + H]

Synthesis of (4-bromooxazol-5-yl)methanol

To a solution of ethyl 4-bromooxazole-5-carboxylate (5.0 g, 22.7 mmol)in THF (100 mL) was added diisobutylaluminium hydride (1.5 M in THF,45.5 mL, 68.2 mmol) dropwise at 0° C. The mixture was stirred at 0° C.for 2 h and then diluted with EA (50 mL). To this mixture was firstadded water (3 mL), then aq. NaOH solution (15%, 3 mL), followed againby water (27 mL), all at 0° C. After warming to r.t., the mixture wasstirred for 15 min, anhydrous MgSO₄ was added and stirring continued foranother 15 min, then the mixture was filtered to remove solids. Thefiltrate was concentrated in vacuo to give crude(4-bromooxazol-5-yl)methanol (2.9 g, 72%) as a yellow solid. LC/MS ESI(m/z): 178 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(3-iodopyridin-4-yl)methanol

m/z (ESI): 236 [M + H](2-(5-((4-bromo-3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorophenyl)methanol

m/z (ESI): 407 [M + H] (2-chloro-4-methoxypyridin-3-yl)methanol

m/z (ESI): 174 [M + H](3-bromo-1-(4-fluoro-2-iodophenyl)-1H-pyrazol-5-yl)methanol

m/z (ESI): 397 [M + H][3-(4-fluoro-2-iodophenyl)-1,2-thiazol-4-yl]methanol

m/z (ESI): 336 [M + H][5-(2-bromo-4-fluorophenyl)-3-methyl-1,2-oxazol-4-yl]methanol

m/z (ESI): 286 [M + H](5-(cyclopropylmethyl)-l-methyl-1H-pyrazol-3-yl)methanol

m/z (ESI): 167 [M + H]

Synthesis of 1-ethyl-3-iodo-1H-pyrazole

To a solution of 3-iodo-1H-pyrazole (10 g, 51.5 mmol) in DMF (50 mL) wasadded iodoethane (12.4 mL, 155 mmol) and K₂CO₃ (21.4 g, 155 mmol) at 25°C. After stirring at 25° C. for 16 h, the reaction mixture was filtered,and the filtrate was diluted with EtOAc (100 mL). This solution waswashed with brine (3×30 mL), dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (0→20% EA in PE) to give 1-ethyl-3-iodo-1H-pyrazole (8.4 g,yield: 73% yield) as a colorless oil. LC/MS (ESI) (m/z): 223 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

3-bromo-1-ethyl-4-iodo-1H-pyrazole

m/z (ESI): 301 [M + H] l-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde

m/z (ESI): 139 [M + H]l-(cyclopropylmethyl)-3-methyl-lH-pyrazole-4-carbaldehyde

m/z (ESI): 165 [M + H]1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 314 [M + H]1-((2-bromo-5-fluoropyridin-3-yl)methyl)-1H-pyrazole-4-carbaldehyde

m/z (ESI): 284 [M + H] 3-(benzyloxy)-1-ethyl-1H-pyrazole

m/z (ESI): 203 [M + H]l-(2,2-difluoroethyl)-3-methyl-lH-pyrazole-4-carbaldehyde

m/z (ESI): 175 [M + H]4-bromo-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile

m/z (ESI): 226 [M + H]l-((2-chloropyridin-3-yl)methyl)-lH-pyrazole-4-carbaldehyde

m/z (ESI): 222 [M + H] 4-iodo-1-isobutyl-1H-pyrazole

m/z (ESI): 251 [M + H]1-((1-(4-fluoro-2-iodophenyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 394 [M + H]1-((2,4-dibromothiazol-5-yl)methyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 347 [M + H]l-((4-bromo-2-methylthiazol-5-yl)methyl)-lH-pyrazole-4-carbaldehyde

m/z (ESI): 286 [M + H] 1-(cyclopropylmethyl)-4-iodo-3-methyl-1H-pyrazole

m/z (ESI): 263 [M + H] 1-(cyclopropylmethyl)-3-methyl-1H-pyrazole

m/z (ESI): 137 [M + H]

Synthesis of 5-chloro-3-iodo-1-methyl-H-pyrazole

To a mixture of 5-chloro-3-iodo-1H-pyrazole (100 mg, 0.440 mmol) andK₂CO₃ (121 mg, 0.880 mmol) in DMF (8 mL) was added methyl iodide (0.03mL, 0.5 mmol) at 25° C. The mixture was then stirred at r.t. for 30 min.The reaction mixture was quenched with ice water, extracted twice intoBA, washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to give crude 5-chloro-3-iodo-1-methyl-1H-pyrazole (100 mg,94% yield) as a yellow liquid. The material can be used as-is, orfurther purified by flash-, high-pressure-, or supercriticalfluid-chromatography to separate possible regioisomers. LC/MS (ESI) m/z:243 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

ethyl 5-bromo-1-(2,2-difluoroethyl)-1H-pyrazole-4-carboxylate

m/z (ESI): 283 [M + H]3-((3-iodo-l-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 328 [M + H](R)-3-((l-(2-(l-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophcnyl)-1H-pyrazol-5-yl)methyl)-1-ethyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 540 [M + H]3-(l-(2-(l,3-dioxolan-2-yl)-4-fluorophenyl)-lH-pyrazole-5-carbonyl)-l-methyl-lH-pyrazole-5-carbonitrile

m/z (ESI): 368 [M + H]

Synthesis of 5-bromo-4-iodo-1-methyl-1H-pyrazole

To a solution of 4-iodo-1-methyl-1H-pyrazole (10.00 g, 48.08 mmol) indry THF (100 mL) at −70° C. was added LDA (2.0 M in THF, 28.8 mL, 57.7mmol) dropwise under N₂ atmosphere over 20 min. After the addition, themixture was stirred at −70° C. for 30 min, then a solution of CBr₄ (19.0g, 57.7 mmol) in THF (40 mL) was added dropwise. The resulting mixturewas stirred at −70° C. for 1 h. The mixture was quenched with sat. NH₄Clsolution, and then diluted with EA (200 mL). The organic layer wasseparated, washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel (2% EA in PE) to give the target product as a brown oil (11g, yield: 80%). LC/MS ESI (m/z): 287 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-bromo-1-cyclobutyl-4-iodo-1H-pyrazole

m/z (ESI): 327 [M + H] 5-bromo-1-ethyl-4-iodo-1H-pyrazole

m/z (ESI): 301 [M + H]5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole

m/z (ESI): 215 [M + H]

Synthesis of 3-bromo-4-iodo-1-methyl-1H-pyrazole

To a solution of 3-bromo-1-methyl-1H-pyrazole (10.0 g, 62.1 mmol) in DMF(32 mL) was added NIS (16.8 g, 74.5 mmol). After the addition, theresulting solution was stirred at 50° C. for 5 h. The mixture wasdiluted with water and extracted into EA, The combined organic phase waswashed with brine (30 mL×4), dried over anhydrous Na₂SO₄, andconcentrated in vacuum. The residue was purified by flash chromatography(0→10% EA in PE) to give 3-bromo-4-iodo-1-methyl-1H-pyrazole (15.0 g,76% yield) as a yellow solid. LC/MS (ESI) m/z: 287 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-ethyl-4-iodo-1H-pyrazole-3-carbonitrile

m/z (ESI): 248 [M + H]5-bromo-l-(cyclopropylmethyl)-4-iodo-3-methyl-IH-pyrazole

m/z (ESI): 341 [M + H]

Synthesis of 3-ethylisoxazole-5-carbaldehyde

To a solution of (3-ethylisoxazol-5-yl)methanol (4.00 g, 31.5 mmol) inDCM (100 mL) was added DMP (16.01 g, 37.75 mmol) at 0° C. and themixture was stirred at r.t. for 1 h (additional equivalents of oxidizingagent may be added to ensure complete oxidation of substrates containingmultiple alcohol groups). The mixture was washed with sat. Na₂S₂O₃ (100mL) and sat. NaHCO₃ (100 mL), dried over anhydrous Na₂SO₄ andconcentrated to dryness. The residue was purified by flashchromatography on silica gel (20 EtOAc in PE) to give3-ethylisoxazole-5-carbaldehyde (3.37 g, yield: 86%) as a yellow oil.LC/MS (EST): m/z=126 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3,5-dicarbaldehyde

m/z (EST): 255 [M + H] 2-chloro-5-fluoropyridine-3-carbaldehyde

m/z (ESI): 160 [M + H]2-(5-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazol-3-yl)acetaldehyde

m/z (ESI): 226 [M + H]3-bromo-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-5-carbaldehyde

m/z (ESI): 395 [M + H]5-(2-bromo-4-fluorophenyl)-3-methylisoxazole-4-carbaldehyde

m/z (ESI): 284 [M + H] methyl1-methyl-3-(2-oxoethyl)-1H-pyrazole-5-carboxylate

m/z (ESI): 183 [M + H] methyl3-formyl-1-methyl-1H-pyrazole-5-carboxylate

m/z (ESI): 169 [M + H]3-(cyclopropylmethyl)-1-methyl-1H-pyrazole-5-carbaldehyde

m/z (ESI): 165 [M + H]5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-3-carbaldehyde

m/z (ESI): 165 [M + H]

Synthesis of 4-(chloromethyl)-1-ethyl-H-pyrazole

To a solution of (1-ethyl-1H-pyrazol-4-yl)methanol (1.40 g, 11.1 mmol)in DCM (15 mL) at 0° C. was added SOCl₂ (3.96 g, 33.3 mmol) dropwiseunder an N₂ atmosphere. After the addition, the mixture was stirred at0° C. for 2 h. The mixture was concentrated to dryness to give crude4-(chloromethyl)-1-ethyl-1H-pyrazole (1.60 g, 10000 yield) as a yellowoil. LC/MS (ESI) m/z: 145 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-bromo-4-(chloromethyl)-1-ethyl-1H-pyrazole

m/z (EST): 223 [M + H]5-bromo-4-(chloromethyl)-1-(difluoromethyl)-1H-pyrazole

m/z (ESI): 245 [M + H]5-(chloromethyl)-1-(4-fluoro-2-iodophenyl)-IH-pyrazole

m/z (ESI): 337 [M + H]

Synthesis of 5-(chloromethyl)-3-ethylisoxazole

To a stirred solution of (3-ethyl-1,2-oxazol-5-yl)methanol (4.10 g, 32.3mmol) in dry DCM (10 mL) was added triethylamine (5.8 mL, 42 mmol),followed by the addition of thionyl chloride (2.8 mL, 39 mmol) at 0° C.over a period of 10 min. After the addition, the reaction mixture wasstirred at r.t. for 5.0 h under N₂. The reaction mixture was cooled to0° C. and quenched with 10% aq. NaCl. The mixture was then extractedwith DCM twice, and the combined extracts were washed with sat. aq.NaHCO₃, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (10→30% EAin PE) to give 5-(chloromethyl)-3-ethyl-1,2-oxazole (4.20 g, yield: 90%)as a yellow oil. LC/MS ESI (m/z): 146 [M+H]⁺.

Synthesis of 3-bromo-1-methylpyrazole-4-carbaldehyde

To a flask of DMF (12.00 mL) was added POCl₃ (12.00 mL) dropwise at 0°C. The resulting mixture was stirred for 30 min at rt. To the abovemixture was added 3-bromo-1-methylpyrazole (4.00 g, 24.8 mmol) dropwiseat r.t. The resulting mixture was then stirred for 3 h at 95° C. Thereaction was quenched with H₂O at rt. The resulting mixture wasconcentrated under reduced pressure. The residue was purified byreverse-phase flash chromatography (C18, 0→30% MeCN in water+0.10% FA)to afford 3-bromo-1-methylpyrazole-4-carbaldehyde (3.94 g, 84%) as alight brown solid. LC/MS ESI (m/z): 189 [M+H]⁺.

Synthesis of 4-bromo-2-methylthiazole-5-carbaldehyde

To a mixture of 2,4-dibromo-1,3-thiazole-5-carbaldehyde (2.00 g, 7.38mmol) and methylboronic acid (486 mg, 8.12 mmol) in 1,4-dioxane (20 mL)was added K₂CO₃ (2.00 g, 14.8 mmol) and Pd(PPh₃)₄ (853 mg, 0.740 mmol)at r.t. The mixture was thrice degassed under N₂ and then stirred at110° C. under an N₂ atmosphere for 12 h. The reaction was cooled tor.t., filtered, and concentrated to dryness. The residue was purified onflash chromatography (silica gel, 250% EtOAc in PE) to give4-bromo-2-methyl-1,3-thiazole-5-carbaldehyde (728 mg, 3100 yield) as ayellow solid. LC/MS (ESI) (m/z): 206 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-[(4-bromo-2-methyl-1,3-thiazol-5-yl)methyl]-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 297 [M + H]4-bromo-5-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)-2-methylthiazole

m/z (ESI): 300 [M + H]4-[4-bromo-2-methyl-1,3-thiazol-5-yl)methyl]-1-ethyl-1H-1,2,3-triazole

m/z (ESI): 287 [M + H]4-[(4-bromo-2-methyl-1,3-thiazol-5-yl)methyl]-1-(cyclopropylmethyl)-1H-1,2,3-triazole

m/z (ESI): 313 [M + H]4-bromo-5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-2-methylthiazole

m/z (ESI): 326 [M + H]1-[(4-bromo-2-methyl-1,3-thiazol-5-yl)methyl]-1H-imidazole-4-carbonitrile

m/z (ESI): 283 [M + H]1-((4-bromo-2-methylthiazol-5-yl)methyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 283 [M + H]4-bromo-5-{[1-(difluoromethyl)-1H-pyrazol-4-yl]methyl}-2-methyl-1,3-thiazole

m/z (ESI): 308 [M + H]4-bromo-5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-methyl-1,3-thiazole

m/z (ESI): 286 [M + H]

Synthesis of 5-bromoisothiazole-4-carboxylic acid

To a solution of isothiazole-4-carboxylic acid (800 mg, 6.20 mmol) inTHF (15 mL) was added t-BuLi (1.3 M in heptane, 10.9 mL, 14.3 mmol) at−78° C. Then a solution of CBr₄ (4.10 g, 12.4 mmol) in THF (10 mL) wasadded dropwise. The mixture was stirred at −78° C. for 2 h. Thisreaction solution was quenched with addition of sat. aq. NH₄Cl andextracted with EtOAc. The aq. layer was adjusted to pH 1 by addition ofaq. HCl (1M) and then extracted with EtOAc. This second organic layerwas dried over anhydrous MgSO₄, filtered, and concentrated in vacuo togive crude 5-bromoisothiazole-4-carboxylic acid (750 mg) as apale-yellow oil. LC/MS ESI (m/z): 208 [M+H]⁺.

Synthesis of 5-iodo-1-methyl-3-vinyl-1H-pyrazole

To a stirred solution of 1-methyl-3-vinyl-1H-pyrazole (4.25 g, 39.30mmol) in THF (40 mL) was added n-BuLi (24 mL, 58.95 mmol, 2.5 M in THF)dropwise via syringe at −78° C. under N₂. After stirring at −78° C. for1 h, a solution of iodine (14.97 g, 58.95 mmol) in THF (25 mL) was addedand the reaction was stirred at −78° C. under N₂ for another 2 h. Thereaction was allowed to warm to 0° C., quenched with sat. aq. NH₄Cl (25mL) and extracted with EtOAc (25 mL×2). The combined organic phases werewashed with Na₂S₂O₃ (20 mL), dried over anhydrous Na₂SO₄ andconcentrated to dryness. The residue was purified by columnchromatography on silica gel (5% EtOAc in PE) to give5-iodo-1-methyl-3-vinyl-1H-pyrazole (2.70 g, 29% yield) as a yellow oil.LC/MS (ESI) (m/z): 235.0 [M+H]⁺.

Synthesis of (5-iodo-1-methyl-1H-pyrazol-4-yl)methanol

To a mixture of 5-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (2.00 g, 8.47mmol) in MeOH (30 mL) was added NaBH₄ (84 mg, 2.5 mmol) at −10° C. Themixture was stirred at 20° C. for 1 h. The mixture was quenched withsat. NH₄Cl (10 mL) and extracted with EA (60 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography on silica gel (5% MeOH inDCM) to afford (5-iodo-1-methyl-1H-pyrazol-4-yl)methanol as alight-yellow solid (840 mg, yield: 41%). LC/MS EST (m/z): 239 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methanol

m/z (ESI): 153 [M + H][1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl]methanol

m/z (ESI): 167 [M + H] (3-bromo-1-methylpyrazol-4-yl)methanol

m/z (ESI): 191 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)methanol

m/z (ESI): 395 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(4-fluoro-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)methanol

m/z (ESI): 413 [M + H][1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl]methanol

m/z (ESI): 333 [M + H](1-ethyl-1H-pyrazol-4-yl)(1-(4-fluoro-2-(hydroxymethyl)phenyl)-3-methyl-1H-pyrazol-5-yl)methanol

m/z (ESI): 331 [M + H] (4-bromo-2-methylthiazol-5-yl)methanol

m/z (ESI): 208 [M + H]

Synthesis of (3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

To a solution of 3-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (2.00 g,8.47 mmol) in dry THF (20 mL) was added DIBAL-H (1.0 M in toluene, 12mL, 12 mmol) dropwise at −70° C. (additional equivalents of reducingagent may be utilized in cases where more than one hydride transfer isrequired). The mixture was stirred at −70° C. for 2 h before quenchingwith sat. aq. NH₄Cl. The resulting mixture was filtered, and the filtercake was washed with THF. The combined filtrates were concentrated underreduced pressure; the residue was diluted with DCM, washed with waterand brine, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by column chromatography on silica gel (0→20% of EA in PE) togive (3-iodo-1-methyl-1H-pyrazol-4-yl)methanol (1.6 g, 79% yield) as ayellow oil. LC/MS ESI (m/z): 239 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazole-5-carbaldehyde

m/z (ESI): 331 [M + H] 5-bromoisothiazole-4-carbaldehyde

m/z (ESI): 192 [M + H][3-(2-bromo-4-fluorophenyl)-1,2-oxazol-4-yl]methanol

m/z (ESI): 272 [M + H](2-(5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorophenyl)methanol

m/z (ESI): 341 [M + H]

Synthesis of 3-chloro-1-ethyl-4-iodo-1H-pyrazole

To a stirred mixture of 3-chloro-4-iodo-1H-pyrazole (55.34 g, 242.2mmol) and Cs₂CO₃ (118.7 g, 364.1 mmol) in DMF (150 mL) was added EtI(29.3 mL, 370 mmol) dropwise at −10° C. After stirring at −10° C. for 3h, the reaction was concentrated. The residue was diluted with EtOAc,washed with brine (150 mL×2), dried over Na₂SO₄ and concentrated todryness. The residue was purified by column chromatography on silica gel(0→20% EA in PE) to give 3-chloro-1-ethyl-4-iodo-1H-pyrazole (37.5 g,60%) as a yellow oil. LC/MS (ESI) m/z: 257 [M+H]⁺.

Synthesis of 4-(chloromethyl)-3-iodo-1-methyl-1H-pyrazole

To a solution of (3-iodo-1-methyl-1H-pyrazol-4-yl)methanol (1.00 g, 4.20mmol) in DCM (20 mL) was added thionyl chloride (0.90 mL, 13 mmol) at 0°C. After addition, the mixture was stirred at r.t. for 3 h, and thenconcentrated to give crude 4-(chloromethyl)-3-iodo-1-methyl-H-pyrazole(1.0 g, 930) as a yellow oil. LCMS (ESI): m/z=257 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

4-(chloromethyl)-1-(cyclopropylmethyl)-1H-pyrazole

m/z (ESI): 171 [M + H]4-(chloromethyl)-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole

m/z (ESI): 185 [M + H]5-bromo-4-(chloromethyl)-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole

m/z (ESI): 263 [M + H] 3-bromo-4-(chloromethyl)-1-methylpyrazole

m/z (ESI): 209 [M + H] 2,4-dibromo-5-(chloromethyl)thiazole

m/z (ESI): 290 [M + H] 4-bromo-5-(chloromethyl)-2-methylthiazole

m/z (ESI): 226 [M + H]

Synthesis of 1-ethyl-3-(propan-2-yl)-1H-pyrazole

To a solution of 1-ethyl-3-iodo-1H-pyrazole (3.20 g, 14.4 mmol) in H₂O(0.5 mL) and 1,4-dioxane (2.5 mL) in a scaled tube were added K₂CO₃(7.97 g, 57.6 mmol), Pd(dppf)Cl₂ (1.05 g, 1.44 mmol). The mixture wasstirred at 100° C. for 16 h, then poured into water (80 mL) andextracted with EA (80 mL). The organic layer was washed with brine (60mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by column chromatography on silica gel (PE/EA=10/1 to 1/1)to give 1-ethyl-3-(prop-1-en-2-yl)-1H-pyrazole (1.2 g, yield: 61% yield)as a white solid. LC/MS (ESI): m/z=137.1 [M+H]⁺.

To a solution of 1-ethyl-3-(prop-1-en-2-yl)-1H-pyrazole (1.0 g, 7.3mmol) in EtOAc (15 mL) was added PtO₂ (0.17 g, 0.73 mmol) and then thismixture was stirred at r.t. for 16 h under H₂ (15 psi). The reactionmixture was filtered, and the filtrate was concentrated to afford crude1-ethyl-3-(propan-2-yl)-1H-pyrazole (800 mg, yield: 79%) as a whitesolid. LC/MS (ESI): m/z=139.1[M+H]⁺.

Synthesis of 1-(difluoromethyl)-1H-pyrazole-4-carbaldehyde

A mixture of 1H-pyrazole-4-carbaldehyde (2.00 g, 20.8 mmol), diethyl(bromodifluoromethyl)phosphonate (9.45 g, 35.3 mmol) and KF (3.63 g,62.4 mmol) in MeCN (20 mL) was stirred at r.t. overnight. The mixturewas filtered and concentrated in vacuo to give a residue, which waspurified by column chromatography on silica gel (10% EtOAc in PE) togive 1-(difluoromethyl)-1H-pyrazole-4-carbaldehyde (2.1 g, 69%) asalight-yellow oil. LC/MS (ESI) m/z: 147 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

ethyl 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-carboxylate

m/z (ESI): 269 [M + H]

Synthesis of 3-chloro-1-(cyclopropylmethyl)-1H-pyrazole

To a solution of 3-chloro-1H-pyrazole (2.00 g, 19.5 mmol) in MeCN (50mL) was added K₂CO₃ (5.40 g, 39.0 mmol) and (bromomethyl)cyclopropane(2.90 g, 21.5 mmol). The reaction mixture was stirred at 80° C. for 12h. The reaction mixture was cooled and filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (0→30% EtOAc in PE) to give3-chloro-1-(cyclopropylmethyl)-1H-pyrazole (2.3 g, 75%) as a colorlessoil. LC/MS (ESI) (m/z): 157 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

3-chloro-1-(2,2-difluoroethyl)-1H-pyrazole

m/z (ESI): 167 [M + H] 1-ethyl-4-iodo-3-(trifluoromethyl)-1H-pyrazole

m/z (ESI): 291 [M + H]3-methyl-1-(propan-2-yl)-1H-pyrazole-5-carbonitrile

m/z (ESI): 150 [M + H]

Synthesis of 5-bromo-1-ethyl-1H-pyrazole-4-carbaldehyde

To a solution of 5-bromo-1-ethyl-1H-pyrazole (100 g, 571 mmol) in TFA(700 mL) at 0° C. was added 1,3,5,7-tetraazaadamantane (120 g, 857mmol). The resulting mixture was stirred at 90° C. for 16 h. Aftercooling to r.t., the mixture was concentrated under reduced pressure toremove most of the TFA. The residue was diluted with DCM (600 mL),washed with sat. NaHCO₃ and brine, dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography onsilica gel (10% EtOAc in PE) to give5-bromo-1-ethyl-1H-pyrazole-4-carbaldehyde as a white solid (60 g,yield: 52%). LC/MS ESI (m/z): 203 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-chloro-3-iodo-(1-methyl-1H-pyrazole-4-carbaldehyde)

m/z (ESI): 271 [M + H]3-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-carbaldehyde

m/z (ESI): 195 [M + H] 3-iodo-1,5-dimethyl-1H-pyrazole-4-carbaldehyde

m/z (ESI): 251 [M + H]3-chloro-1-(cyclopropylmethyl)-1H-pyrazole-4-carbaldehyde

m/z (ESI): 185 [M + H] 3,5-dibromo-1-methyl-1H-pyrazole-4-carbaldehyde

m/z (ESI): 267 [M + H] 3-bromo-1-(tert-butyl)-1H-pyrazole-4-carbaldehyde

m/z (ESI): 231 [M + H]1-ethyl-3-(propan-2-yl)-1H-pyrazole-4-carbaldehyde

m/z (ESI): 167 [M + H] 1,3-diethyl-1H-pyrazole-4-carbaldehyde

m/z (ESI): 153 [M + H]

Synthesis of 3-bromo-1-(tert-butyl)-1H-pyrazole

To a mixture of 3-bromo-1H-pyrazole (3.00 g, 20.4 mmol) and2-methylpropan-2-ol (5 mL) was added H₂SO₄ (1.98 mL, 20.4 mmol) slowlyat r.t. The mixture was heated at 100° C. for 16 h. The reaction mixturewas diluted with H₂O (20 mL) and then extracted with ethyl acetate (20mL). The organic layer was washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered, concentrated, and then purified by silicagel chromatography (0-100% EtOAc in PE) to give3-bromo-1-tert-butyl-1H-pyrazole (1.4 g, 34% yield) as a yellow oil.LC/MS (ESI) m/z: 203.0 [M+H]⁺.

Synthesis of 1,3-diethyl-1H-pyrazole

A mixture of 3-ethenyl-1-ethyl-1H-pyrazole (1.00 g, 8.18 mmol) andplatinum dioxide (0.190 g, 0.82 mmol) in EtOAc (10 mL) was stirred atr.t. under H₂ (15 psi) overnight. This mixture was filtered, and thefiltrate was concentrated. The residue was purified by columnchromatography on silica gel (0→100% of EtOAc in PE) to give1,3-diethyl-1H-pyrazole (1.00 g, 98% yield) as a colorless oil. LC/MS(ESI) (m/z): 125 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

3-ethyl-5-iodo-1-methyl-1H-pyrazole

m/z (ESI): 237 [M + H]

Synthesis of 3-(bromomethyl)-2-chloro-5-fluoropyridine

To a solution of (2-chloro-5-fluoropyridin-3-yl)methanol (4.0 g, 25mmol) in DMF (20 mL) was added tribromophosphine (2.4 mL, 26 mmol)dropwise at 0° C. After stirring at 25° C. for 1 h, the mixture wasbasified to pH 7 with sat. NaHCO₃, and extracted with EA (30 mL×3). Thecombined organic phase was dried over anhydrous Na₂SO₄ and concentratedin vacuo. The residue was purified by prep-TLC (8% EA in PE) to give3-(bromomethyl)-2-chloro-5-fluoropyridine (2.7 g, 46% yield) as acolorless oil. LC/MS ESI (m/z): 224 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

3-(bromomethyl)-2-chloro-6-methoxypyridine

m/z (ESI): 236 [M + H]3-(2-bromo-4-fluorophenyl)-4-(bromomethyl)isothiazole

m/z (ESI): 352 [M + H] 3-(bromomethyl)-5-cyclobutyl-1-methyl-1H-pyrazole

m/z (ESI): 229 [M + H]

Synthesis of 1-cyclobutyl-4-iodo-H-pyrazole

A mixture of 4-iodo-1H-pyrazole (10.0 g, 51.6 mmol), bromocyclobutane(20.9 g, 155 mmol) and K₂CO₃ (28.5 g, 206 mmol) in DMF (200 mL) washeated at 70° C. for 12 h. The reaction mixture was filtered, and thefiltrate was extracted with EA (300 ml×2). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by column chromatography on silica gel (0→5%EtOAc in PE) to give the target product (9.73 g, 76% yield) as a yellowoil. LC/MS ESI (m/z): 249 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-(cyclopropylmethyl)-4-iodo-1H-pyrazole

m/z (ESI): 249 [M + H] ethyl5-bromo-1-cyclobutyl-1H-pyrazole-4-carboxylate

m/z (ESI): 273 [M + H] ethyl 5-bromo-1-(2-fluoroethyl)-1H-pyrazole-4-carboxylate

m/z (ESI): 265 [M + H]

Synthesis of (4-fluoro-2-iodophenyl)hydrazine

To a mechanically stirred solution of 4-fluoro-2-iodoaniline (5.0 g, 21mmol) in AcOH (10 mL) was slowly added conc. HCl (40 mL). The solutionquickly became a thick suspension. The reaction was then cooled to 0° C.in an ice bath and treated slowly dropwise with a solution of sodiumnitrite (1.63 g, 23.6 mmol) in water (8 mL). The reaction was stirredfor 1 h, then a solution of SnCl₂ (8.46 g, 44.5 mmol) in conc. HCl (8mL) was added slowly. The reaction was allowed to warm to r.t. over 2 h.The suspension was filtered, washed with water and dried under vacuum togive crude (4-fluoro-2-iodophenyl)hydrazine hydrochloride (4.1 g, yield:77%) as a gray solid. LC/MS (ESI) m/z: 253 [M+H]⁺.

Synthesis of 5-bromo-4-(bromomethyl)-1-ethyl-1H-pyrazole

To a stirred solution of (5-bromo-1-ethyl-1H-pyrazol-4-yl)methanol (4.00g, 19.5 mmol) and triphenylphosphine (6.14 g, 23.4 mmol) in dry DCM (50mL) was added a solution of tetrabromomethane (7.76 g, 23.4 mmol) in DCMdropwise at 0° C. After the addition, the reaction mixture was stirredat r.t. for 24 h. The reaction mixture was concentrated in vacuo and theresidue was purified by silica gel column chromatography (eluent:PE/EtOAc 50/1 to 10/1) to give5-bromo-4-(bromomethyl)-1-ethyl-1H-pyrazole (3.0 g, 57% yield) as awhite solid. LC/MS ESI (m/z): 267 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-bromo-4-(bromomethyl)-1-cyclobutyl-1H-pyrazole

m/z (ESI): 293 [M + H]5-bromo-4-(bromomethyl)-1-(2,2-difluoroethyl)-1H-pyrazole

m/z (ESI): 303 [M + H]5-bromo-4-(bromomethyl)-1-(2-fluoroethyl)-1H-pyrazole

m/z (ESI): 285 [M + H]3-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

m/z (ESI): 316 [M + H]

Synthesis of 2-bromo-3-(bromomethyl)-5-fluoropyridine

A mixture consisting of 2-bromo-5-fluoro-3-methylpyridine (2.00 g, 10.5mmol), AIBN (52 mg, 0.32 mmol) and NB₃S (2.44 g, 13.7 mmol) in DCE (20mL) was thrice degassed with N_(z) and heated to 85° C. with stirringfor 1 h. After cooling to r.t., the mixture was quenched with water,diluted with EtOAc, and washed with brine. The final organic layer wasdried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuoto provide a residue, which was purified by silica gel flash columnchromatography (PE:EA=50:1) to give2-bromo-3-(bromomethyl)-5-fluoropyridine (1.20 g, 42%) as a white solid.LC-MS ESI (m/z): 268 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

4-bromo-3-(bromomethyl)-1-isopropyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 306 [M + H]4-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 278 [M + H]

Synthesis of 3-bromo-1-(difluoromethyl)-4-iodo-1H-pyrazole

To a solution of 3-bromo-4-iodo-1H-pyrazole (5.42 g, 19.9 mmol) anddiethyl (bromodifluoromethyl)phosphonate (7.95 g, 29.8 mmol) inacetonitrile (50 mL) was added potassium fluoride (2.3 g, 40 mmol). Thereaction was stirred at 40° C. for 3 h. The reaction was cooled to r.t.,diluted with DCM (50 mL), washed with water (50 mL) and brine (50 mL),dried over Na₂SO₄ and concentrated to dryness. The residue was purifiedby chromatography on silica gel (15% EtOAc in PE) to give3-bromo-1-(difluoromethyl)-4-iodo-1H-pyrazole (5.12 g, 80% yield) as awhite solid. LC/MS (ESI) m/z: 323 [M+H]⁺.

Synthesis of (3-cyano-1-methyl-1H-pyrazol-5-yl)boronic acid

To a solution of 1-methyl-1H-pyrazole-3-carbonitrile (1.0 g, 9.3 mmol)in THF (15 mL) was added LDA (2 M in THF, 4.7 mL, 9.3 mmol) dropwiseunder the atmosphere of N₂ at −78° C. After stirring for 0.5 h at −78°C., trimethyl borate (1.9 g, 19 mmol) in THF (2 mL) was added dropwise.After stirring at −78° C. for 1 h, the reaction was quenched with sat.aq. ammonium chloride. The reaction was diluted with EtOAc and washedfirst with H₂O and then brine. The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residuewas purified by silica gel column chromatography (0→80% EtOAc in PE) togive (3-cyano-1-methyl-1H-pyrazol-5-yl)boronic acid (800 mg, 57% yield)as a yellow oil. LC/MS ESI (m/z): 152 [M+H]⁺.

Synthesis of 3-(azidomethyl)-2-bromopyridine

To a solution of 2-bromo-3-(chloromethyl)pyridine (1.15 g, 5.58 mmol) inMeCN (20 mL) was added NaN₃ (1.09 g, 16.8 mmol) at r.t. The mixture wasstirred at 40° C. overnight, then partitioned between EtOAc (20 mL) andwater (20 mL). The organic phase was washed with brine (20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography (silica gel, 0→33% EA in PE) to give3-(azidomethyl)-2-bromopyridine (955 mg, 80% yield over 2 steps) as ayellow oil. LC/MS (ESI) m/z: 213 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

4-(azidomethyl)-3-iodo-1-methyl-1H-pyrazole

m/z (ESI): 264 [M + H] 3-(azidomethyl)-2-bromo-5-fluoropyridine

m/z (ESI): 231 [M + H] 5-(azidomethyl)-3-ethyl-1,2-oxazole

m/z (ESI): 153 [M + H]

Synthesis of 2-(5-bromo-1-ethyl-1H-pyrazol-4-yl)acetonitrile

To a solution of 5-bromo-4-(chloromethyl)-1-ethyl-1H-pyrazole (5.00 g,22.4 mmol) in DMSO (50 mL) was added NaCN (2.20 g, 44.7 mmol) at 25° C.After stirring at 25° C. for 2 h, the mixture was treated with EtOAc andH₂O. The organic layer was separated, washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby column chromatography on silica gel (20% EtOAc in PE) to give2-(5-bromo-1-ethyl-1H-pyrazol-4-yl)acetonitrile (4.5 g, yield: 94%) as alight-yellow oil. LC/MS ESI (m/z): 214 [M+H]⁺.

Synthesis of 1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)ethanol

To a solution of 5-bromo-1-ethyl-1H-pyrazole-4-carbaldehyde (10.00 g,49.25 mmol) in THF (120 mL) was added methylmagnesium bromide (18.8 mL,56.4 mmol, 3.0 M in THF) dropwise at 0° C. over 10 min. The resultingmixture was stirred at 0° C. for 1 h. The mixture was quenched with sat.NH₄Cl (30 mL) at 0° C. and then extracted with EA (100 mL×3), thecombined extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (20% EtOAc in PE) to give1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)ethanol as a light-yellow solid (9.28g, 86% yield). LC/MS ESI (m/z): 219 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

cyclopropyl(3-iodo-1-methyl-1H-pyrazol-5-yl)methanol

m/z (ESI): 279 [M + H]1-(2-(1-((5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 415 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(4-fluoro-1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)methanone

m/z (ESI): 425 [M + H] 1-(5-bromoisothiazol-4-yl)prop-2-yn-1-ol

m/z (ESI): 218 [M + H](1-ethyl-1H-pyrazol-4-yl)(3-fluoro-1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)methanone

m/z (ESI): 347 [M + H]1-[3-(4-fluoro-2-iodophcnyl)-1,2-thiazol-4-yl]prop-2-yn-1-ol

m/z (ESI): 360 [M + H]1-((5-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 326 [M + H]3-(1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 340 [M + H]

Synthesis of 3-(bromomethyl)-2-chloro-5-methoxy pyridine

To a solution of 2-chloro-5-methoxy-3-methylpyridine (500 mg, 3.17 mmol)in CCl₄ (12 mL) was added NBS (565 mg, 3.17 mmol) and benzoyl peroxide(76.8 mg, 0.317 mmol). The mixture was stirred at 80° C. for 3 h, thenpoured into water (80 mL), and the extracted with EA (80 mL×3). Thecombined organic layers were washed with brine (60 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel eluted (1→10% EtOAc in PE) to give2-chloro-3-(dibromomethyl)-5-methoxypyridine (200 mg, yield: 20%) as awhite solid. LC/MS (ESI): m/z=315.8 [M+H]⁺.

To a solution of 2-chloro-3-(dibromomethyl)-5-methoxypyridine (200 mg,0.634 mmol) in THF (4 mL) was added diethoxyphosphinous acid (0.161 mL,1.27 mmol), DIPEA (164 mg, 1.27 mmol) and then this mixture was stirredat r.t. for 16 h. The mixture was poured into water (80 mL) andextracted with EA (80 mL×3). The combined organic layers were washedwith brine (60 mL), dried with Na₂SO₄, filtered, and concentrated invacuo. This residue was purified by column chromatography on silica geleluted (1→10% EtOAc in PE) to give3-(bromomethyl)-2-chloro-5-methoxypyridine (100 mg, yield: 67%) as awhite solid. LC/MS (ESI): m/z=236 [M+H]⁺.

Synthesis of 1-(3-iodo-1-methyl-1H-pyrazol-4-yl)-prop-2-yn-1-ol

To a solution of 3-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (1.00 g,4.24 mmol) in THF (7 mL) at 0° C. was added ethynylmagnesium bromide(12.7 mL, 6.36 mmol) dropwise. The mixture was stirred at r.t. for 2 h.The reaction was quenched with sat. aq. NH₄Cl (13 mL) and extracted withEA (15 mL×3). The organic layer was separated, washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography on silica gel (20→90% EA in PE) togive 1-(3-iodo-1-methyl-1H-pyrazol-4-yl)prop-2-yn-1-ol (780 mg, 70%) asa white solid. LC-MS (ESI) m/z: 262.9 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-(2-chloro-5-fluoropyridin-3-yl)prop-2-yn-1-ol

m/z (ESI): 186 [M + H] 1-(2-bromo-4-fluorophenyl)prop-2-yn-1-ol

m/z (ESI): 229 [M + H]1-(2-(1-((5-bromo-1-cyclobutyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 419 [M + H]1-(2-(1-((5-bromo-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 429 [M + H]1-[2-(1-{[5-bromo-1-(2-fluoroethyl)-1H-pyrazol-4-yl]methyl}-1H-imidazol-2-yl)-5-fluorophenyl]ethan-1-ol

m/z (ESI): 411 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)methanone

m/z (ESI): 407 [M + H]1-(3-chloro-1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)prop-2-yn-1-ol

m/z (ESI): 415 [M + H](1-((2-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)(cyclopropyl)methanol

m/z (ESI): 264 [M + H]1-(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)ethanol

m/z (ESI): 393 [M + H] methyl3-(cyclopropyl(hydroxy)methyl)-1-methyl-1H-pyrazole-5-carboxylate

m/z (ESI): 211 [M + H]

Synthesis of 4-fluoro-2-iodobenzamide

To a solution of 4-fluoro-2-iodobenzoic acid (5.00 g, 18.8 mmol) in DCM(100 mL) was added oxalyl chloride (5.00 g, 39.4 mmol), followed by theaddition of DMF (0.07 mL, 0.9 mmol) at 0° C. After the addition, theresulting mixture was stirred at 25° C. for 2 h. The mixture wasconcentrated in vacuo to dryness to give crude 4-fluoro-2-iodobenzoylchloride as a yellow oil.

To a solution of 4-fluoro-2-iodobenzoyl chloride in dry DCM (50 mL)cooled to 0° C., was added a pre-cooled solution of aq. NH₃ (14 mL, 370mmol, 28% in H₂O) dropwise over 10 min. The internal temperature wasmaintained below 5° C. during the addition. The resulting mixture wasstirred at r.t. for 4 h and then concentrated to dryness. The residualwhite solids were triturated with water and PE, and then dried in avacuum oven to give target product 4-fluoro-2-iodobenzamide (11 g, 92%yield over 2 steps) as a white solid. LC/MS (ESI): m/z=266 [M+H]⁺.

Synthesis of 3-bromo-5-methoxy-1-methyl-1H-pyrazole-4-carbaldehyde

To a stirred solution of 3,5-dibromo-1-methyl-1H-pyrazole-4-carbaldehyde(5.00 g, 20.8 mmol) in MeOH (40 mL), was added sodium methanolate (12.5mL, 62.5 mmol, 5.0 M in methanol) and the resulting mixture was stirredat 60° C. for 1 h. After 1 h, the reaction mixture was concentrated invacuo to remove the solvent. The residue was diluted with sat. aq. NH₄Cl(30 mL) and EtOAc (30 mL), and then extracted with EtOAc (3×30 mL). Theorganic phases were combined, washed with brine (30 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give crude3-bromo-5-methoxy-1-methyl-1H-pyrazole-4-carbaldehyde (3.31 g, yield:59%) as a light-yellow solid. LC/MS (ESI) (m/z): 219 [M+H]⁺.

Synthesis of 1-(2,4-dibromothiazol-5-yl)prop-2-yn-1-ol

To a solution of 2,4-dibromo-1,3-thiazole-5-carbaldehyde (2.0 g, 7.3mmol) in THE (20 mL) at −78° C. was added ethynylmagnesium bromide (7.3mL, 7.3 mmol, 1 M in THF) under an N₂ atmosphere. After the addition,the mixture was stirred at −78° C. for 2 h. The reaction was quenchedwith sat. aq. solution of ammonium chloride (30 mL). The reactionmixture was concentrated in vacuo and diluted with DCM (30 mL). Then themixture was washed with brine (30 mL) and dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the residue, which waspurified by flash chromatography (30% EtOAc in PE) to give1-(2,4-dibromothiazol-5-yl)prop-2-yn-1-ol (1.5 g, 68%) as a white solid.LC/MS ESI (m/z): 296 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-(3,5-difluoro-2-iodophenyl)ethan-1-ol

m/z (ESI): 285 [M + H]

Synthesis of 1-[(1-methylcyclopropyl)methyl]-1H-pyrazole-4-carbaldehyde

To a solution of (1-methylcyclopropyl)methanol (0.56 mL, 5.8 mmol) andTEA (0.89 mL, 6.4 mmol) in DCM (20 mL) was added methanesulfonylchloride (0.49 mL, 6.4 mmol). The mixture was stirred at 0° C. for 1 h.This solution was added to a mixture of 1H-pyrazole-4-carbaldehyde (836mg, 8.70 mmol) and K₂CO₃ (1.60 g, 11.6 mmol) in DMF (10 mL) and thereaction was stirred at 0° C. for 2 h. The mixture was filtered andconcentrated in vacuo to give a residue which was purified by columnchromatography on silica gel (25% EtOAc in PE) to give1-[(1-methylcyclopropyl)methyl]-1H-pyrazole-4-carbaldehyde (350 mg,yield: 37%) as a light-yellow solid. LC/MS ESI (m/z): 165 [M+H]⁺.

Synthesis of methyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate

To a solution of 5-(methoxycarbonyl)-1-methyl-1H-pyrazole-3-carboxylicacid (5.70 g, 30.9 mmol) in THF (80 mL) at 0° C. under N₂, was slowlyadded BH₃.THF (61.9 mL, 61.9 mmol, 1 N). The reaction was allowed towarm to r.t. over 30 min and then heated to 65° C. for 4 h. Aftercooling to r.t., MeOH (12 mL) was slowly added, and then the solvent wasremoved under reduced pressure. The residue was re-dissolved in MeOH (12mL), stirred for 20 min at r.t., and then then evaporated to dryness.The residue was diluted with water and extracted with DCM (50.0 mL×3).The combined organic phases were washed with brine (50 mL), dried overanhydrous sodium sulfate, filtered, and concentrated. The crude mixturewas then purified via silica gel chromatography (33→100% EA in PE) togive methyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate (3.2 g,yield: 61%) as a white solid. LC-MS ESI (m/z): 171 [M+H]⁺.

Synthesis of ethyl 5-ethyl-1,2-thiazole-3-carboxylate

To a solution of ethyl 2,4-dioxohexanoate (3.00 g, 17.4 mmol) in toluene(30 mL) was added ammonium acetate (3.36 g, 43.6 mmol), AcOH (3.0 mL, 52mmol). The reaction mixture was stirred at 80° C. for 18 h, allowed tocool, and then concentrated under reduced pressure. The residue wasdiluted with water, and the pH was adjusted to 8 with 10% aq. Na₂CO₃.The resulting mixture was extracted with EtOAc (2×50 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (0-20% EtOAc in PE) to give ethyl 4-amino-2-oxohex-3-enoate(1.2 g, 40%) as a pale-yellow oil. LC/MS (ESI): m/z=172 [M+H]⁺.

To a solution of ethyl 4-amino-2-oxohex-3-enoate (1.30 g, 7.59 mmol) inTHF (15 mL) was added phosphorus pentasulfide (0.84 g, 3.8 mmol). Thereaction mixture was stirred at r.t. overnight. The mixture wasconcentrated, and the residue was dissolved in EA (50 mL). This solutionwas cooled to 0° C. and H₂O₂ (30%, 5 mL) was added. The mixture wasstirred at r.t. for 10 min and then extracted with EtOAc (50 mL×2). Thecombined organic extracts were dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (0-30% EtOAc in PE) to give ethyl5-ethyl-1,2-thiazole-3-carboxylate (0.75 g, 53%) as a white solid. LC/MS(ESI): m/z=186 [M+H]⁺.

Synthesis of 1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)ethanone

To a solution of 1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)ethanol (9.28 g,42.4 mmol) in DCM (50 mL) was added DMP (21.5 g, 50.8 mmol) portion-wiseat 0° C. over 10 min. After the addition, the mixture was stirred at 0°C. for another 10 min. The mixture was adjusted to pH 8 with sat. NaHCO₃and then extracted with EA (100 mL×3). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (20% EtOAc in PE) togive 1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)ethanone as light-yellow oil(8.6 g, yield: 93%). LC/MS ESI (m/z): 217 [M+H]⁺.

Synthesis of 4-bromo-3-methyl-1-(propan-2-yl)-1H-pyrazole-5-carbonitrile

A mixture of 3-methyl-1-(propan-2-yl)-1H-pyrazole-5-carbonitrile (470mg, 3.15 mmol), TFA (0.25 mL, 3.4 mmol) and NBS (673 mg, 3.78 mmol) inMeCN (20 mL) was stirred at r.t. for 1 h. The reaction mixture wasdiluted with EtOAc (30 mL), washed with sat. Na₂S₂O₃ (20 mL), dried overNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby flash chromatography on silica gel (25% EtOAc in PE) to give4-bromo-3-methyl-1-(propan-2-yl)-1H-pyrazole-5-carbonitrile (460 mg, 64%yield) as a light-yellow solid. LC/MS (ESI) m/z: 228 [M+H]⁺.

Synthesis of 5-bromo-N-methoxy-N-methylisothiazole-4-carboxamide

To a solution of 5-bromoisothiazole-4-carboxylic acid (700 mg, crude) inDCM (15 mL), were added HATU (1.6 g, 4.4 mmol), TEA (1.0 g, 10 mmol) andN,O-dimethylhydroxylamine hydrochloride (427 mg, 4.40 mmol). Afterstirring at 25° C. for 16 h, the reaction was diluted with DCM. Theresulting mixture was washed with H₂O, and then brine. The organic layerwas dried over anhydrous Na₂SO₄, filtered, and concentrated undervacuum. The residue was purified by silica gel column chromatography,(0→17% EtOAc in PE) to give5-bromo-N-methoxy-N-methylisothiazole-4-carboxamide (220 mg, 14% yieldover 2 steps) as a yellow oil. LC/MS ESI (m/z): 251 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-ethyl-N-methoxy-N-methylisoxazole-3-carboxamide

m/z (ESI): 185 [M + H]

Synthesis of 3-bromo-5-fluoro-2-(trimethylstannyl)pyridine

A mixture of 2,3-dibromo-5-fluoropyridine (1.0 g, 3.9 mmol),hexamethyldistannane (1.35 g, 4.12 mmol) and Pd(PPh₃)₄ (0.23 g, 0.20mmol) in toluene (50 mL) was heated to 110° C. under N₂ for 16 h. Themixture was concentrated, diluted with EtOAc (50 mL), washed with brine(30 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by neutral Al₂O₃ chromatography (100% petroleum ether) toafford 3-bromo-5-fluoro-2-(trimethylstannyl)pyridine (1.2 g, 90% yield)as a colorless oil. LC/MS (EST) m/z: 340 [M+H]⁺.

Synthesis of methyl3-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxylate

Under a nitrogen atmosphere, 9-borabicyclo[3.3.1]nonane (31.34 mL, 15.67mmol) was added to a solution of methyl3-ethenyl-1-methyl-1H-pyrazole-5-carboxylate (1.50 g, 9.04 mmol) indioxane (50 mL) at 0° C., and the mixture was stirred at 100° C. for 1h. Water (10 mL), aq. sodium hydroxide (3.50 mL, 31.0 mmol, 10% inwater) and hydrogen peroxide (3.2 mL, 10% in water) were successivelyadded dropwise to the reaction mixture at 0° C. The mixture was stirredat r.t. for 0.5 h, then water (20 mL) and ethyl acetate (30 mL) wereadded. The layers were separated, and the aq. layer was extracted withethyl acetate (20 mL). The combined organic layers were washed withbrine (20 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (1.6% MeOH in DCM) to afford methyl3-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxylate (1.10 g, 66%) as awhite solid. LC/MS ESI (m/z): 185 [M+H]⁺.

Synthesis of methyl 2-chloro-4-methoxynicotinate

A mixture of methyl 2,4-dichloropyridine-3-carboxylate (2.40 g, 11.6mmol) and sodium methoxide (2.06 g, 11.6 mmol) in MeOH (20 mL) wasrefluxed under N₂ for 16 h. The mixture was filtered through celite andthe filtrate was diluted with EA (30 mL). This solution was washed withbrine, dried over anhydrous Na₂SO₄, and concentrated. The residue waspurified by column chromatography on silica gel (0→30% EA in PE) to givemethyl 2-chloro-4-methoxynicotinate (1.70 g, yield: 72%) as a whitesolid. LC/MS (ESI) (m/z): 202 [M+H]⁺.

Synthesis of potassium (E)-3-cyano-1-ethoxy-1-oxopent-2-en-2-olate

To a stirred solution of t-BuOK (8.10 g, 72.4 mmol) and 18-crown-6 (1.91g, 7.24 mmol) in THF (60 mL) was added a solution of diethyl oxalate(10.57 g, 72.35 mmol) in THF (10 mL) via syringe at 0° C. under N₂. Thereaction was heated to 60° C., and then a solution of butyronitrile(5.00 g, 72.3 mmol) in THF (10 mL) was added and stirring continued at60° C. for 30 min. The reaction was evaporated to dryness to give crudepotassium (E)-3-cyano-1-ethoxy-1-oxopent-2-en-2-olate (14.20 g, yield:93%) as a yellow solid. LC/MS ESI (m/z): 170 [M+H]⁺.

Synthesis of 2-(2-bromo-4-fluorophenyl)-1H-imidazole

To a mixture of 2-bromo-4-fluorobenzaldehyde (50.00 g, 246.3 mmol) andoxalaldehyde (52.56 mL, 492.6 mmol, 40% in H₂O) in EtOH (200 mL) wasadded NH₃—H₂O (113.8 mL, 738.9 mmol, 25% in H₂O) dropwise under N₂atmosphere at r.t. After the addition, the resulting mixture wasdegassed, heated to 50° C. and stirred for 72 h. The reaction mixturewas concentrated in vacuo and the residue was diluted with EA, washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(PE/EA=3:1 to 2:1) to afford 2-(2-bromo-4-fluorophenyl)-1H-imidazole(35.0 g, 59% yield) as a yellow solid. LC/MS ESI (m/z): 241 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

2-(4-fluoro-2-iodophenyl)-4-methyl-1H-imidazole

m/z (ESI): 303 [M + H]

Synthesis of[5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl]methanol

To a solution of5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole-4-carbaldehyde (1.80g, 7.41 mmol) in EtOH (15 mL) was added NaBH₄ (0.33 g, 9.6 mmol) at 0°C. This mixture was stirred at 0° C. for 1 h. The reaction mixture wasconcentrated, diluted with H₂O (10 mL) and extracted with EtOAc (15mL×3). The combined organic solutions were washed with brine (15 mL),dried over anhydrous Na₂SO₄, and then concentrated to give crude(5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methanol (1.4 g,yield: 77%) as a light-yellow solid. LC-MS (ESI) m/z: 245 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

[1-(4-fluoro-2-iodophenyl)-1H-pyrazol-5-yl]methanol

m/z (ESI): 319 [M + H]3-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

m/z (ESI): 254 [M + H]

Synthesis of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane

To a mixture of 2-bromo-5-fluorobenzaldehyde (10.0 g, 49.3 mmol) andethane-1,2-diol (9.16 g, 148 mmol) in toluene (100 mL) at 25° C. wasadded 4-methylbenzenesulfonic acid (1.69 g, 9.87 mmol) in one portionunder an N₂ atmosphere. After the addition, the mixture was stirred at120° C. for 16 h. The resulting mixture was cooled to 2-5° C., and thendiluted with water and EtOAc. The organic layer was separated, washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by column chromatography on silica gel(20→30% EtOAc in PE) to give the target product as a yellow oil (10.0 g,yield: 82%). LC/MS ESI (m/z): 247 [M+H]⁺.

Synthesis of 5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole

To a stirred solution ofcyclopropyl(3-iodo-1-methyl-1H-pyrazol-5-yl)methanol (1.0 g, 3.6 mmol)in DCM (18 mL) was added TES (4.20 g, 36.0 mmol) and TFA (2.7 mL, 36mmol) at 0° C. The reaction was stirred at r.t. overnight. The reactionwas concentrated to dryness. The residue was purified by flashchromatography (0→10% EtOAc in PE) to give5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole (0.60 g, 51% yield) asa yellow solid. LC/MS (ESI) (m/z): 263 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

methyl 3-(cyclopropylmethyl)-1-methyl-1H-pyrazole-5-carboxylate

m/z (ESI): 195 [M + H]

Synthesis of (5-ethyl-1,2-thiazol-3-yl)methanol

To a solution of ethyl 5-ethyl-1,2-thiazole-3-carboxylate (750 mg, 4.05mmol) in THF (15 mL) was added DIBAL-H (13.5 mL, 20.2 mmol) at 0° C. Thereaction mixture was stirred at r.t. for 2 h and then quenched bysequential addition of MeOH (0.5 mL) and then water (15 mL). Theresulting mixture was extracted with EtOAc (2×50 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (0→50% EtOAc in PE) to give(5-ethyl-1,2-thiazol-3-yl)methanol (510 mg, 88%) as a colorless oil.LC/MS (EST): m/z=144 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3,5-diyl)dimethanol

m/z (ESI): 259 [M + H] (1-(4-fluoro-2-iodophenyl)-1H-imidazol-5-yl)methanol

m/z (ESI): 319 [M + H](3-(2-bromo-4-fluorophenyl)isothiazol-4-yl)methanol

m/z (ESI): 288 [M + H](3-(cyclopropylmethyl)-1-methyl-1H-pyrazol-5-yl)methanol

m/z (ESI): 167 [M + H]

Synthesis of 5-fluoro-2-(1H-imidazol-2-yl)benzaldehyde

n-BuLi (21.54 mL, 53.86 mmol, 2.5 N) and N,N-dimethylformamide (6.25 mL,80.79 mmol) were added dropwise simultaneously via two differentsyringes over 30 min to a solution of2-(2-bromo-4-fluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(10.00 g, 26.93 mmol) in anhydrous THF (20 mL) while maintaining theinternal temperature at −78° C. After the addition, the mixture wasstirred at −78° C. for 10 min before quenching with sat. aq. NH₄Cl. Theresulting mixture was warmed slowly to r.t. and acidified to pH 6 with 2N HCl. The mixture was then extracted with ether (150 mL). The organiclayer was washed with water and brine, dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica-gel (30% EtOAc in PE) to afford5-fluoro-2-(1-{[2(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)benzaldehyde(6.0 g, 70% yield) as an orange oil. LC/MS ESI (m/z): 321 [M+H]⁺.

To a flask of TFA (209 mL) was added5-fluoro-2-(1-{[2(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)benzaldehyde(45.0 g, 141 mmol) portion-wise at 20° C. The resulting solution wasstirred at r.t. for 6 h, and the reaction mixture was concentrated invacuo to remove most of the TFA. The residue was poured slowly into sat.aq. NaHCO₃ at 0° C. The resulting mixture was then extracted with EA(3×200 mL), and the combined extracts were dried over anhydrous Na₂SO₄,and concentrated in vacuo. The residue was purified by flash columnchromatography on silica-gel (0→3% MeOH in DCM) to give5-fluoro-2-(1H-imidazol-2-yl)benzaldehyde (23.0 g, 86% yield) as a whitesolid. LC/MS ESI (m/z): 191 [M+H]⁺.

Synthesis of methyl5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-3-carboxylate

A mixture of 5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole (2.50 g,9.54 mmol), triethylamine (2.90 g, 28.6 mmol), MeOH (50 mL), andPd(dppf)Cl₂ (698 mg, 0.950 mmol) was thrice degassed under a COatmosphere and then stirred under a CO balloon at 60° C. for 12 h. Themixture was cooled to r.t., filtered, and concentrated to dryness. Theresidue was purified by column chromatography on silica gel (PE:EA=5:1)to give methyl 5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-3-carboxylate(1.50 g, 81% yield) as a brown oil. LC/MS (ESI) (m/z): 195.1 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

methyl2-(5-((4-bromo-3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorobenzoate

m/z (ESI): 435 [M + H]

Synthesis of 1-((4-bromothiazol-5-yl)methyl)-1H-imidazole-4-carbonitrile

To a mixture of (4-bromo-1,3-thiazol-5-yl)methanol (480 mg, 2.40 mmol),1H-imidazole-4-carbonitrile (276 mg, 2.90 mmol) and triphenylphosphine(1.3 g, 4.9 mmol) in dry THF (30 mL) was added DIAD (0.98 mL, 4.9 mmol)dropwise at 0° C. over 10 min. After the addition, the reaction mixturewas stirred at r.t. for 2 h. The mixture was concentrated in vacuo andthe residue was purified by flash chromatography on silica gel (30%EtOAc in PB) to give1-((4-bromothiazol-5-yl)methyl)-1H-imidazole-4-carbonitrile (220 mg,yield: 33%) as a light-yellow solid. LC/MS ESI (m/z): 269 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-((4-bromopyridin-3-yl)methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 263 [M + H]1-((2-bromopyridin-3-yl)methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 263 [M + H]1-((2-bromopyridin-3-yl)methyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 263 [M + H]1-((2-bromopyridin-3-yl)methyl)-2-methyl-1H-imidazole-4-carbonitrile

m/z (ESI): 277 [M + H]1-{[1-(4-fluoro-2-iodophenyl)-1H-pyrazol-5-yl]methyl}-1H-imidazole-4-carbonitrile

m/z (ESI): 394 [M + H]1-[(5-iodo-1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrazole-4-carbonitrile

m/z (ESI): 314 [M + H]

Synthesis of 5-(2-bromo-4-fluorophenyl)-1,3,4-oxathiazol-2-one

To a solution of 2-bromo-4-fluorobenzamide (4.43 g, 20.3 mmol) intoluene (50 mL) was added chloro(chlorosulfanyl)methanone (2.53 mL, 30.5mmol). The mixture was stirred at 100° C. for 2 h, concentrated invacuo, and the residue was purified by column chromatography on silicagel (0→50% EtOAc in PE) to give5-(2-bromo-4-fluorophenyl)-1,3,4-oxathiazol-2-one (3.90 g, 69% yield) asa white solid. LC/MS (ESI) m/z: 276 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-(4-fluoro-2-iodophenyl)-1,3,4-oxathiazol-2-one

m/z (ESI): 324 [M + H]

Synthesis of 5-ethyl-1,2-thiazole-3-carbaldehyde

To a solution of (5-ethyl-1,2-thiazol-3-yl)methanol (510 mg, 3.56 mmol)in DCM (15 mL) was added MnO₂ (3.10 g, 35.6 mmol). The reaction mixturewas stirred at r.t. for 20 h. After filtration, the filtrate wasconcentrated under reduced pressure to give5-ethyl-1,2-thiazole-3-carbaldehyde (120 mg, 24%) as a pale-yellow oil.LC/MS (ESI): m/z=142 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-(4-fluoro-2-iodophenyl)-1H-imidazole-5-carbaldehyde

m/z (ESI): 317 [M + H]3-(2-bromo-4-fluorophenyl)-1,2-oxazole-4-carbaldehyde

m/z (ESI): 270 [M + H]3-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-5-carbaldehyde

m/z (ESI): 175 [M + H]

Synthesis of methyl3-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-5-carboxylate

Under a nitrogen atmosphere, diethylaminosulfur trifluoride (0.40 mL,3.0 mmol) was slowly added to a crude solution of methyl1-methyl-3-(2-oxoethyl)-1H-pyrazole-5-carboxylate (1.5 g, 2.9 mmol) inDCM (20 mL) at 0° C. The reaction was stirred at this temperature for0.5 h, then quenched with sat. aq. NaHCO₃ (50 mL). The resulting mixturewas extracted with DCM (3×10 mL). The combined extracts were washedsequentially with water (1×30 mL) and brine (30 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by prep-TLC (0→50% EtOAc in PE) to provide methyl3-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-5-carboxylate (500 mg, 85%)as a white solid. LC/MS ESI (m/z): 205 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

2-bromo-3-((4-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-5-fluoropyridine

m/z (ESI): 306 [M + H](R)-1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazole

m/z (ESI): 347 [M + H]

Synthesis of (R)-1-(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)ethan-1-ol

A mixture of methyl[2-(methylamino)ethyl]amine (0.41 mL, 3.8 mmol),(1R)-1-(5-fluoro-2-iodophenyl)ethan-1-ol (5.0 g, 19 mmol), 1H-pyrazole(1.09 mL, 22.6 mmol), K₂CO₃ (5.19 g, 37.6 mmol) and CuI (60 mg, 1.9mmol) in NMP (150 mL) in a sealed tube was stirred at 120° C. under N₂for 18 h. The reaction mixture was poured into water (100 mL) and thenextracted with EtOAc (100 mL×2). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by column chromatography (silica gel, 1→10% ethyl acetatein petroleum ether) to afford(1R)-1-[5-fluoro-2-(TH-pyrazol-1-yl)phenyl]ethan-1-ol (3.6 g, 93%) as ayellow oil. LC/MS (ESI) m/z: 207.1 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(R)-1-(2-(3-chloro-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 241 [M + H](R)-1-(5-fluoro-2-(3-methoxy-1H-pyrazol-1-yl)phenyl)ethan-1-ol

m/z (ESI): 237 [M + H]

Synthesis of ethyl 5-cyclobutyl-1-methyl-1H-pyrazole-3-carboxylate

To a solution of ethyl 4-cyclobutyl-2,4-dioxobutanoate (6.2 g, 31 mmol)in acetic acid (15 mL) was added methylhydrazine (3.6 g, 31 mmol) andthe resulting mixture was stirred at 100° C. for 3 h. After 3 h, thereaction mixture was cooled to r.t. and concentrated in vacuo to removethe solvent to give the residue, which was diluted with toluene (20 mL)and concentrated in vacuo. The residue was purified by silica gelchromatography (0→50% EA in PE) to give ethyl5-cyclobutyl-1-methyl-1H-pyrazole-3-carboxylate (4.2 g, 20%) as a yellowoil. LC/MS ESI (m/z): 209 [M+H]⁺.

Synthesis of 3-ethyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole

To a stirred solution of 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (5.00g, 36.7 mmol) and 1-nitropropane (7.00 g, 78.6 mmol) in toluene (40 mL)was added phenyl isocyanate (17.0 mL, 119 mmol), followed by theaddition of triethylamine (2.94 mL, 21.2 mmol). The reaction mixture washeated to 120° C. and stirred for 24 h. After cooling to r.t., thereaction mixture was quenched with 1 mL of water, and the mixture wasstirred at r.t. for 1 h. The precipitates were removed by filtration,and the filtrate was concentrated. The residue was purified by columnchromatography on silica gel (0→20% EtOAc in PE) to give3-ethyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole (10.0 g, 61%yield) as a yellow syrup. LC/MS ESI (m/z): 212 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

3-(cyclopropylmethyl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole

m/z (ESI): 238 [M + H]3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole

m/z (ESI): 342 [M + H]

Synthesis of (2-(3-chloro-1H-pyrazol-1-yl)-5-fluorophenyl)methanol

To a solution of (5-fluoro-2-iodophenyl)methanol (25.0 g, 99.2 mmol) intoluene (250 mL) were added 3-chloro-1H-pyrazole (11.2 g, 109 mmol),K₂CO₃ (27.4 g, 198.4 mmol) and CuI (1.9 g, 9.9 mmol). The reaction wasstirred at 120° C. under N₂ for 12 h. The reaction was filtered andconcentrated. The residue was purified by flash chromatography (5-25%EtOAc in PE) to give(2-(3-chloro-1H-pyrazol-1-yl)-5-fluorophenyl)methanol (21.1 g, 85%yield) as a white solid. LC/MS (ESI) (m/z): 227 [M+H]⁺.

Synthesis of1-[(2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carbonitrile

A mixture of 3-(azidomethyl)-2-bromopyridine (955 mg, 4.48 mmol) and2-chloroprop-2-enenitrile (0.90 mL, 11 mmol) in water (30 mL) wasstirred at 80° C. for 12 h. The reaction was cooled to r.t., extractedwith DCM (20 mL), washed with sat. brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography (silica gel, 0→100% EA in PE) to give1-[(2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole-4-carbonitrile (639mg, 54% yield) as a white solid. LC/MS (ESI) m/z: 264 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazole-4-carbonitrile

m/z (ESI): 315 [M + H]

Synthesis of [5-bromo-1-(2-fluoroethyl)-1H-pyrazol-4-yl]methanol

To a solution of ethyl5-bromo-1-(2-fluoroethyl)-1H-pyrazole-4-carboxylate (3.10 g, 11.3 mmol)in THF (50 mL) was added DIBAL-H (22.6 mL, 22.6 mmol, 1 M in toluene)dropwise at 0° C. over 10 min. After the addition, the resultingsolution was stirred at r.t. for another 3 h. After cooling to 0° C.,the reaction mixture was treated with EtOAc (100 mL) and 1 N HCl (100mL), and the organic layer was separated, and the aq. layer wasextracted with EtOAc (150 mL). The combined organics were concentratedin vacuo and the residue was purified by flash chromatography (silicagel, 0→50 of EtOAc in PE) to give[5-bromo-1-(2-fluoroethyl)-1H-pyrazol-4-yl]methanol (2.1 g, 83% yield)as a white solid. LC-MS(ESI) found: 223 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)methanol

m/z (ESI): 177 [M + H]

Synthesis of 3-bromo-4-[(4-ethylimidazol-1-yl)methyl]-1-methylpyrazole

To a stirred mixture of 4-ethyl-1H-imidazole (0.73 g, 7.6 mmol) in DMF(5.00 mL) was added NaH (0.22 g, 9.1 mmol) in portions at 0° C. Theresulting mixture was stirred for 30 min at 0° C. To the above mixturewas added 3-bromo-4-(chloromethyl)-1-methylpyrazole (1.91 g, 9.11 mmol)in DMF (5 mL) dropwise at 0° C. The resulting mixture was stirred foradditional 1 h at r.t., then quenched with H₂O. The resulting mixturewas purified directly by reverse-phase flash chromatography (C18, 0→40%MeCN in water+1% aq. NH₃) to afford3-bromo-4-[(4-ethylimidazol-1-yl)methyl]-1-methylpyrazole (1.9 g, 93%)as a light brown oil. LC-MS (ESI) m/z: 269 [M+H]⁺.

Synthesis of (5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)methanol

To a solution of ethyl5-bromo-1-(difluoromethyl)-1H-pyrazole-4-carboxylate (2.00 g, 7.43 mmol)in THF (30 mL) was added DIBAL-H (18.6 mL, 18.6 mmol, 1 M in toluene) at−78° C. over 30 min. During the addition, the internal temperature wasmonitored to stay below −60° C. The reaction was stirred for 1 h at −78°C., then quenched by slowly adding into aq. HCl (1M) at 0° C. Themixture was extracted with EtOAc twice. The combined extracts werewashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel (30 of EtOAc in PE) to give(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)methanol (1.5 g, 89% yield)as a colorless oil. LC/MS ESI (m/z): 227 [M+H]⁺.

Synthesis of (4-bromooxazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

To a solution of (4-bromooxazol-5-yl)methanol (2.90 g, 16.3 mmol) in DCM(5 mL) was added Dess-Martin periodinane (10.4 g, 24.4 mmol). Thereaction was stirred at r.t. for 2 h, filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatography(0→30% EtOAc in PE) to give 4-bromooxazole-5-carbaldehyde (2.49 g, 87%yield) as a light-yellow solid. To a solution of1-ethyl-4-iodo-1H-pyrazole (3.14 g, 14.2 mmol) in THF (30 mL) was addedisopropylmagnesium chloride-lithium chloride complex (13.1 mL, 17.0mmol, 1.3 M in THF) dropwise at −10° C. The mixture was stirred at r.t.for 1 h, then cooled to −10° C. A solution of4-bromooxazole-5-carbaldehyde (2.49 g, 14.2 mmol) in 10 mL THF was addeddropwise. The ice bath was removed and stirring was continued at r.t.for 1 h. The reaction was quenched with sat. aq. NH₄Cl (20 mL), and thenextracted with EA (3×20 mL). The combined organic phases were washedwith water (20 mL) and brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography (0→10% MeOH in DCM) to give(4-bromooxazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol (1.21 g, 31%yield) as a light-yellow solid. LC/MS ESI (m/z): 272 [M+H]⁺.

Synthesis of(E)-1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-3-(dimethylamino)prop-2-en-1-one

A mixture of 1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)ethan-1-one (4.00 g,18.4 mmol) and DMF-DMA (80 mL) was stirred at 110° C. for 12 h. Aftercooling to r.t., the mixture was concentrated in vacuo by oil pump toobtain crude(E)-1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-3-(dimethylamino)prop-2-en-1-oneas alight-yellow solid (2.6 g, yield: 51%). LC/MS ESI (m/z): 272 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(E)-N′-(4-fluoro-2-iodobenzoyl)-N,N-dimethylformohydrazonamide

m/z (ESI): 336 [M + H]

Synthesis of5-((4-bromothiazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

A mixture of5-[(dibromo-1,3-thiazol-5-yl)methyl]-1-methyl-1H-pyrazole-3-carbonitrile(0.700 g, 1.93 mmol), Pd/C (0.07 g, 10% wt) in MeOH (20 mL) was stirredat 50° C. for 2 h under 1 atm of H₂. The reaction mixture was filtered,and the filtrate was concentrated in vacuo. The residue was purified byflash chromatography (0→25% EA in PE) to give5-((4-bromothiazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(0.45 g, 78% yield) as a colorless oil. LC/MS (ESI) (m/z): 283 [M+H]⁺.

Synthesis of(5-bromoisothiazol-4-yl)(1-ethyl-1H-1,2,3-triazol-4-yl)methanol

To a solution of 1-(5-bromoisothiazol-4-yl)prop-2-yn-1-ol (100 mg, 0.46mmol) in t-BuOH (1 mL) and H₂O (1 mL) was added sodium(R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate(4.5 mg, 0.02 mmol), azidoethane (1.2 M in THF, 2.0 mL, 2.3 mmol) andCuSO₄ (3.6 mg, 0.02 mmol) under N₂ at 25° C. After stirring at 50° C.for 16 h, the reaction was diluted with EtOAc. The resulting mixture waswashed with H₂O, brine and dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated. The residue was purified byflash chromatography (silica gel, 0→100% EA in PE) to give(5-bromoisothiazol-4-yl)(1-ethyl-1H-1,2,3-triazol-4-yl)methanol (60 mg,45% yield) as a yellow oil. LC/MS (ESI) m/z: 289 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(1-ethyl-1H-1,2,3-triazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 334 [M + H]4-ethyl-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazole

m/z (ESI): 318 [M + H](1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI) 360 [M + H](2-chloro-5-fluoropyridin-3-yl)(1-ethyl-1H-1,2,3-triazol-4-yl)methanol

m/z (ESI): 257 [M + H](2,4-dibromothiazol-5-yl)(1-ethyl-1H-1,2,3-triazol-4-yl)-methanol

m/z (ESI): 369 [M + H](2-chloro-5-fluoropyridin-3-yl)[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methanol

m/z (ESI): 283 [M + H](3-chloro-1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methanol

m/z (EST): 512 [M + H][1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl](dibromo-1,3-thiazol-5-yl)methanol

m/z (ESI): 393 [M + H](1-ethyl-1H-1,2,3-triazol-4-yl)[3-(4-fluoro-2-iodophenyl)-1,2-thiazol-4-yl]methanol

m/z (ESI): 431 [M + H]

Synthesis of 1-((3-iodopyridin-4-yl)methyl)-1H-imidazole-4-carbonitrile

To a solution of PPh₃ (1.43 g, 5.45 mmol) in THF (16 mL) at 0° C. wasadded a solution of DIAD (1.1 g, 5.45 mmol) in THF (16 mL) under N₂atmosphere. After the addition, the mixture was stirred at 0° C. until awhite solid precipitated. To this mixture was added1H-imidazole-4-carbonitrile (304 mg, 3.27 mmol) in THF (8 mL), followedby (3-iodopyridin-4-yl)methanol (640 mg, 2.72 mmol) in THF (8 mL). Theresulting mixture was stirred at r.t. for 3 h. The mixture wasconcentrated under reduced pressure. The residue was diluted with DCM(60 mL), then washed with water and brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography on silica gel (50% EtOAc in PE) to1-((3-iodopyridin-4-yl)methyl)-1H-imidazole-4-carbonitrile (890 mg,yield: 53%) as a pale-yellow oil. LC-MS (ESI): m/z 311 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 314 [M + H]1-((2-chloro-5-fluoropyridin-3-yl)methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 237 [M + H]1-[(dibromo-1,3-thiazol-5-yl)methyl]-1H-imidazole-4-carbonitrile

m/z (ESI): 347 [M + H]

Synthesis of 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carbonitrile

To a stirred flask of conc. H₂SO₄ (25 mL) was added NaNO₂ (2.93 g, 42.5mmol) at 0° C. in several portions. The mixture was heated to 50° C. andstirred at this temperature for 1 h. This nitrite mixture was cooled to0° C. and set aside. Separately, conc. H₂SO₄ (3.97 g, 40.5 mmol) wasadded to a solution of 4-fluoro-2-iodoaniline (9.60 g, 40.5 mmol) inAcOH (40 mL) at r.t. This solution was added dropwise to the originalnitrite mixture at 0° C. After addition was complete, the mixture washeated to 50° C. for 1 h. The reaction mixture was then added to asuspension of ethyl 2,3-dicyanopropanoatc (9.24 g, 60.8 mmol) andanhydrous NaOAc (49.82 g, 607.6 mmol) in H₂O (100 mL) at 5° C. Afterstirring for 15 h at 15° C., the reaction mixture was diluted with waterand extracted with DCM (250 mL). The organic layer was stirredvigorously with 30% aq. NH₄OH (150 mL) for 2 h. The organic phaseseparated, dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by flash chromatography (0→70% EtOAc inPE) to give 5-amino-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carbonitrile(11 g, 83%) as a brown solid. LC/MS ESI (m/z): 329 [M+H]⁺.

A solution of5-amino-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carbonitrile (12.0 g,36.6 mmol) and isopentyl nitrite (12.8 g, 110 mmol) in THF (150 mL) at25° C. was heated to 70° C. and stirred for 16 h. The reaction wasdiluted with EtOAc. The resulting mixture was washed with H₂O, and thenbrine. The organic layer was dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under vacuum. The residue waspurified by silica gel column chromatography, eluted with PE/EA (0-20%)to give 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carbonitrile (6.0 g, 52%yield) as a clear oil. LC/MS ESI (m/z): 314 [M+H]⁺.

Synthesis of 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-5-carbaldehyde

To a suspension of (4-fluoro-2-iodophenyl)hydrazine (4.10 g, 16.3 mmol)in EtOH (100 mL) was added[(1E)-4,4-dimethoxy-3-oxobut-1-en-1-yl]dimethylamine (2.82 g, 16.3mmol). The resulting mixture was heated at reflux for 48 h and thenconcentrated. To a solution of the crude residue in acetone (50 mL) wasadded 6 N HCl (10 mL). The resulting solution was stirred at r.t. for 30min, and then was partitioned between ethyl acetate and water. Theorganic extract was washed with water, sat. sodium bicarbonate, andbrine, and then dried over anhydrous sodium sulfate. The residue wasconcentrated to dryness to give crude1-(4-fluoro-2-iodophenyl)-1H-pyrazole-5-carbaldehyde (4.50 g, yield:88%) as a black oil. LC/MS (ESI) m/z: 317 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

ethyl 1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazole-5-carboxylate

m/z (ESI): 375 [M + H]5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 500 [M + H]

Synthesis of 3,5-difluoro-2-iodo-N-methoxy-N-methylbenzamide

A mixture of 3,5-difluoro-2-iodobenzoic acid (11.3 g, 39.8 mmol), EDCI(9.92 g, 51.7 mmol), HOBt (6.99 g, 51.7 mmol), methoxy(methyl)amine(2.92 g, 47.9 mmol) and DIPEA (15.40 g, 119.4 mmol) in DMF (40 mL) wasstirred at r.t. for 2 h. The mixture was concentrated, diluted with EA(80 mL) and washed with sat. NaHCO₃ (40 mL×3). The combined organiclayers were separated, washed by brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flash columnchromatography on silica gel to give3,5-difluoro-2-iodo-N-methoxy-N-methylbenzamide (12 g, 92%) aslight-yellow solid. LC-MS (ESI): m/z 328 [M+H]⁺.

Synthesis of (5-cyclobutyl-1-methyl-1H-pyrazol-3-yl)methanol

To a solution of ethyl 5-cyclobutyl-1-methyl-1H-pyrazole-3-carboxylate(4.20 g, 20.2 mmol) in THF (40 mL) was added diisobutylaluminium hydride(33.6 mL, 50.4 mmol, 1.5 M in THF) dropwise at −78° C. The mixture wasstirred at −78° C. for 1 h. After 1 h, the reaction mixture was dilutedby EA (20 mL), then water (2 mL), aq. NaOH solution (15%, 2 mL) andwater (5 mL) was added in sequence at 0° C. After warming to r.t.,anhydrous MgSO₄ was added, and stirring was continued for 15 min. Themixture was filtered, and the filtrate was concentrated in vacuo to givecrude (5-cyclobutyl-1-methyl-1H-pyrazol-3-yl)methanol (2.86 g, 85%) as ayellow oil. LC/MS ESI (m/z): 167 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(5-bromo-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methanol

m/z (ESI): 241 [M + H]

Synthesis of (3-ethylisoxazol-5-yl)methanol

To a solution of 3-ethyl-5-[(oxan-2-yloxy)methyl]-1,2-oxazole (17.4 g,82.4 mmol) in MeOH (10 mL) was added Amberlyst 15 (26 mg, 83 mmol). Themixture was stirred vigorously at 45° C. for 6 h. Filtration and removalof solvent in vacuum gave a red residue, which was purified by columnchromatography on silica gel (15→30% EtOAc in PE) to give(3-ethyl-1,2-oxazol-5-yl)methanol (8.05 g, yield: 77%) as a pale-yellowoil. LC/MS ESI (m/z): 128 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(3-(cyclopropylmethyl)isoxazol-5-yl)methanol

m/z (EST): 154 [M + H] (3-(2,2-difluoroethyl)isoxazol-5-yl)methanol

m/z (ESI): 164 [M + H]

Synthesis of 3-(bromomethyl)-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole

To a stirred solution of(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-3-yl)methanol (410 mg, 2.47mmol) in DCM (10 mL) was added dropwise a solution of phosphoroustribromide (2.00 g, 7.40 mmol) in DCM (5 mL) at 0° C. under N₂. Thereaction was stirred at 0° C. for 2 h, washed with sat. NaHCO₃ (30 mL),dried over anhydrous Na₂SO₄ and evaporated to dryness. The residue waspurified by column chromatography on silica gel eluted with PE/EtOAc(9:1→4:1) to give3-(bromomethyl)-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole (285 mg, 50%yield) as a yellow oil. LC/MS (ESI) (m/z): 229 [M+H]⁺.

Synthesis of5-((2-chloropyridin-3-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

To a Solution of 3-(bromomethyl)-2-chloropyridine (2.07 g, 10.1 mmol),(3-cyano-1-methyl-1H-pyrazol-5-yl)boronic acid (1.52 g, 10.0 mmol),Pd(PPh₃)₄ (0.81 g, 0.70 mmol) in toluene (20 mL) and EtOH (4 mL), wasadded Na₂CO₃ (2.13 g, 20.1 mmol). The reaction was thrice degassed withN₂, and then stirred at 100° C. overnight. The mixture was cooled tor.t., filtered, and concentrated in vacuo. The residue was purified byflash chromatography (0→50% EtOAc in PE) to give5-((2-chloropyridin-3-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(675 mg, 29%) as a yellow solid. LC/MS ESI (m/z): 233 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-((2-chloro-5-fluoropyridin-3-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 251 [M + H]4-bromo-3-((2-chloropyridm-3-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 311 [M + H]5-(2-bromobenzyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 276 [M + H]5-((3-(2-bromo-4-fluorophenyl)isothiazol-4-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 377 [M + H]

Synthesis of (5-bromo-1-cyclobutyl-1H-pyrazol-4-yl)methanol

At −60° C., to a solution of ethyl5-bromo-1-cyclobutyl-1H-pyrazole-4-carboxylate (1.9 g, 7.0 mmol) in THF(20 mL), was added DIBAL-H (1M in toluene, 20.9 mL, 20.9 mmol) dropwiseat −60° C. Then the mixture was stirred at 0° C. for 3 h. The reactionmixture was diluted with EA (20 mL), and water (1 mL), and then 15%sodium hydroxide solution (1 mL) and water (2.5 mL) were addedsequentially. After warming to r.t., anhydrous magnesium sulfate wasadded and stirring was continued for 15 min. The resulting mixture wasfiltered, the filtrate was washed with sat. aq. NH₄Cl and brine, driedover anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residuewas purified by column chromatography on silica gel (0→10% EtOAc in PE)to give (5-bromo-1-cyclobutyl-1H-pyrazol-4-yl)methanol (1.6 g, 15%) as alight-yellow oil. LC/MS ESI (m/z): 231 [M+H]⁺.

Synthesis of 3-(benzyloxy)-5-bromo-1-ethyl-1H-pyrazole

To a stirred solution of 3-(benzyloxy)-1-ethyl-1H-pyrazole (11.5 g, 56.9mmol) in THF (200 mL) was added n-BuLi (27.3 mL, 68.3 mmol, 2.5 M inTHF) at −78° C. under N₂. After stirring at −78° C. for 1 h, a solutionof CBr₄ (22.6 g, 68.2 mmol) in THF (50 mL) was added. The reaction wasstirred at −78° C. for another 1.5 h, then quenched with sat. NH₄Cl (50mL) and concentrated in vacuo. The residue was purified by flashchromatography (0→25% EtOAc in PE) to give3-(benzyloxy)-5-bromo-1-ethyl-1H-pyrazole (8.3 g, 52% yield) as a yellowoil. LC/MS ESI (m/z): 281.0 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(R)-3-chloro-1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazole-5-carbaldehyde

m/z (ESI): 389 [M + H](R)-1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazole-5-carbaldehyde

m/z (ESI): 375 [M + H]

Synthesis of(3-bromo-1-methyl-1H-pyrazol-4-yl)(5-ethylisoxazol-3-yl)methanone

To a stirred solution of 3-bromo-4-iodo-1-methyl-1H-pyrazole (500 mg,1.74 mmol) in THF (10 mL) was added i-PrMgBr (2.1 mL, 2.1 mmol, 1 M inTHF) at 0° C. under N₂. After stirring at 0° C. for 1 h, a solution of5-ethyl-N-methoxy-N-methyl-1,2-oxazole-3-carboxamide (360 mg, 1.95 mmol)in THF (2 mL) was added dropwise. The reaction was stirred at 0° C. foranother 1 h, then quenched with sat. NH₄Cl (10 mL) and extracted withEtOAc (30 mL×2). The combined organic phases were washed with brine (20mL), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by column chromatography on silica gel (25% EtOAc in PE) togive 3-(3-bromo-1-methyl-1H-pyrazole-4-carbonyl)-5-ethyl-1,2-oxazole(400 mg, 77% yield) as a yellow oil. LC/MS (ESI) (m/z): 284.3 [M+H]⁺.

Synthesis of2-bromo-3-((4-ethyl-1H-1,2,3-triazol-1-yl)methyl)-5-fluoropyridine

To a solution of 1-butyne (ca. 0.2 M, 12 mL) was added3-(azidomethyl)-2-bromo-5-fluoropyridine (350 mg, 1.52 mmol) and CuI (57mg, 0.30 mmol). The mixture was stirred at r.t. for 1 h then filteredthrough celite. The filtrate was concentrated in vacuo to get a residue,which was purified by silica gel column chromatography (PE:EA=10:1 to3:1) to give2-bromo-3-[(4-ethyl-1H-1,2,3-triazol-1-yl)methyl]-5-fluoropyridine(130.0 mg, 30% yield) as a white solid. LC/MS (ESI): m/z=285 [M+H]⁺.

Synthesis of(3-bromo-1-methyl-1H-pyrazol-4-yl)(3-ethylisoxazol-5-yl)methanol

To the mixture of 3-bromo-4-iodo-1-methyl-1H-pyrazole (1.43 g, 4.98mmol) in TH (10 mL) was added isopropylmagnesium bromide (1 M in THF,5.48 mL, 5.48 mmol) slowly under N_(z) at 0° C. The mixture was stirredat 0° C. for 1 h. To this mixture was added a solution of3-ethylisoxazole-5-carbaldehyde (0.62 g, 5.0 mmol) in dry THF (3 mL)dropwise at 0° C. over 10 min and the resulting mixture was stirred at0° C. for another 1 h. The reaction mixture was quenched by ice-waterand then extracted with EtOAc twice. The combined extracts wereconcentrated and the residue was purified by column chromatography onsilica gel (PE:EA=3:1) to give(3-bromo-1-methyl-1H-pyrazol-4-yl)(3-ethylisoxazol-5-yl)methanol (900mg, yield: 63%) as a yellow oil. LC/MS ESI (m/z): 286 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(5-bromo-1-ethyl-1H-pyrazol-4-yl)(5-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 411 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(2-bromopyridin-3-yl)methanol

m/z (ESI): 360 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)(3-ethyl-1-methyl-1H-pyrazol-5-yl)methanol

m/z (ESI): 299 [M + H]5-[(dibromo-1,3-thiazol-5-yl)(hydroxy)methyl]-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 377 [M + H](3-chloro-1-ethyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 367 [M + H](5-bromo-1-cyclobutyl-1H-pyrazol-4-yl)(5-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 437 [M + H] ethyl5-((3-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl)isoxazole-3-carboxylate

m/z (ESI): 330 [M + H](3-(benzyloxy)-5-bromo-1-ethyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 517 [M + H][5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl](5-chloro-3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 485 [M + H](3-ethyl-1-methyl-1H-pyrazol-5-yl)(1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methanol

m/z (ESI): 441 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(3-iodopyridin-4-yl)methanol

m/z (ESI): 408 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(4-fluoro-2-iodophenyl)-1H-imidazol-5-yl)methanol

m/z (ESI): 491 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)(1-ethyl-3-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 299 [M + H](1-ethyl-1H-pyrazol-4-yl)(3-iodo-1,5-dimethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 347 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)(5-ethyl-1,2-thiazol-3-yl)methanol

m/z (ESI): 302 [M + H](2-chloropyridin-3-yl)(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methanol

m/z (ESI): 265 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)(3-ethylisothiazol-5-yl)methanol

m/z (ESI): 302 [M + H](2-chloropyridin-3-yl)(1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 278 [M + H](1-(2-((R)-1-(benzyloxy)ethyl)-4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl)(1-ethyl-3-methoxy-1H-pyrazol-4-yl)methanol

m/z (ESI): 501 [M + H](3-bromo-1-ethyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 411 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)(1,3-diethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 313 [M + H](3-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methanol

m/z (ESI): 347 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)(1-isobutyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 313 [M + H](3-bromo-1-(4-fluoro-2-iodophenyl)-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 491 [M + H](dibromo-1,3-thiazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 368 [M + H]5-((1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 438 [M + H]3-((5-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbaldehyde

m/z (ESI): 415 [M + H](5-bromo-1-methyl-1H-pyrazol-4-yl)(1-ethyl-5-iodo-1H-pyrazol-4-yl)methanol

m/z (ESI): 411 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-3-yl)methanol

m/z (ESI): 325 [M + H]

Synthesis of 5-bromo-4-((1-ethyl-H-1,2,3-triazol-4-yl)methyl)isothiazole

To a solution of(5-bromoisothiazol-4-yl)(1-ethyl-H-1,2,3-triazol-4-yl)methanol (60 mg,0.20 mmol) in TFA (3 mL) was added TES (193 mg, 1.60 mmol). The mixturewas heated to 70° C. and stirred for 2 h. The reaction mixture wasconcentrated, diluted with sat. aq. NaHCO₃, and extracted with EtOAc.The combined organic phases were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography (silica gel, 0→40% EA in PE) to give5-bromo-4-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl)isothiazole (50 mg, 88%yield) as a yellow oil. LC/MS (EST) m/z: 273 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-iodo-1-methyl-1H-pyrazole

m/z (ESI): 343 [M + H]3-bromo-4-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole

m/z (ESI): 283 [M + H]5-[(dibromo-1,3-thiazol-5-yl)methyl]-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 361 [M + H]3-chloro-1-ethyl-4-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole

m/z (ESI): 351 [M + H]2,4-dibromo-5-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)thiazole

m/z (ESI): 364 [M + H]5-bromo-1-ethyl-4-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole

m/z (ESI): 395 [M + H]1-ethyl-4-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazole

m/z (ESI): 318 [M + H]5-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 328 [M + H]3-iodo-1-methyl-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)methyl)-1H-pyrazole

m/z (ESI): 371 [M + H]1-(cyclopropylmethyl)-4-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazole

m/z (ESI): 344 [M + H]5-bromo-1-(cyclopropylmethyl)-4-[(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl]-3-methyl-1H-pyrazole

m/z (ESI): 435 [M + H]5-bromo-4-((5-chloro-3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole

m/z (ESI): 469 [M + H]5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(4-fluoro-2-iodophenyl)-1H-1,2,3-triazole

m/z (ESI): 476 [M + H]5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carbonitrile

m/z (ESI): 500 [M + H]4-bromo-3-ethyl-5-((1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole

m/z (ESI): 503 [M + H]4-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-3-iodopyridine

m/z (ESI): 392 [M + H]4-bromo-3-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)pyridine

m/z (ESI): 344 [M + H]5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)pyrimidin-4-ol

m/z (ESI): 283 [M + H]5-bromo-3-(1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 593 [M + H]5-bromo-3-((2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 579 [M + H]5-bromo-3-(1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-4-fluoro-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 611 [M + H]5-bromo-3-((2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-4-fluoro-1H-pyrazol-1-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 597 [M + H]2-chloro-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl)-5-fluoropyridine

m/z (ESI): 241 [M + H] 3-chloro-1-ethyl4-((1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazole

m/z (ESI): 445 [M + H]4-[(dibromo-1,3-thiazol-5-yl)methyl]-1-ethyl-1H-1,2,3-triazole

m/z (ESI): 351 [M + H]3-bromo-4-((3-chloro-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole

m/z (ESI): 339 [M + H]4-[(3-bromo-1-methyl-1H-pyrazol-4-yl)methyl]-1-(2,2-difluoroethyl)-3-methyl-1H-pyrazole

m/z (ESI): 319 [M + H]3-bromo-1-(difluoromethyl)-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1H-pyrazole

m/z (ESI): 305 [M + H]3-[(3-bromo-1-methyl-1H-pyrazol-4-yl)methyl]-5-ethyl-1,2-thiazole

m/z (ESI): 286 [M + H](R)-1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole

m/z (ESI): 499 [M + H]1-ethyl-4-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole

m/z (ESI): 385 [M + H]2-chloro-3-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-5-fluoropyridine

m/z (ESI): 267 [M + H]1-(cyclopropylmethyl)-4-[(dibromo-1,3-thiazol-5-yl)methyl]-1H-1,2,3-triazole

m/z (ESI): 377 [M + H]2-chloro-3-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methyl)pyridine

m/z (ESI): 249 [M + H](R)-4-((1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl)methyl)-1-(cyclopropylmethyl)-1H-1,2,3-triazole

m/z (ESI): 482 [M + H](R)-1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazole

m/z (ESI): 495 [M + H]2,4-dibromo-5-{[1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl]methyl}-1,3-thiazole

m/z (ESI): 390 [M + H](R)-1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazole

m/z (ESI): 481 [M + H]3-bromo-4-{[3-chloro-1-(cyclopropylmethyl)-1H-pyrazol-4-yl]methyl}-1-methyl-1H-pyrazole

m/z (ESI): 329 [M + H]2-chloro-3-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)pyridine

m/z (ESI): 262 [M + H](R)-1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-3-(difluoromethyl)-5-((1-ethyl-3-methoxy-1H-pyrazol-4-yl)methyl)-1H-pyrazole

m/z (ESI): 485 [M + H]2-chloro-3-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)pyridine

m/z (ESI): 248 [M + H]3-bromo-4-{[1-ethyl-3-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1-methyl-1H-pyrazole

m/z (ESI): 311 [M + H]3-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-5-ethylisoxazole

m/z (ESI): 270 [M + H]4-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 294 [M + H]5-bromo-3-((2-(5-((1-ethyl-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 515 [M + H]5-bromo-3-(1-(2-(5-((1-ethyl-1H-pyrazol-4-yl)methyl)-3-fluoro-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 533 [M + H]5-bromo-3-((2-(3-chloro-5-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 535 [M + H]3-bromo-5-((1-ethyl-1H-pyrazol-4-yl)methyl)-1-(4-fluoro-2-iodophenyl)-1H-pyrazole

m/z (ESI): 475 [M + H]2,4-dibromo-5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,3-thiazole

m/z (ESI): 352 [M + H]5-((1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 422 [M + H]3-((5-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-5-carbonitrile

m/z (ESI): 266 [M + H]3-bromo-4-((3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole

m/z (ESI): 319 [M + H]3-bromo-4-((3-(cyclopropylmethyl)-1-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole

m/z (ESI): 309 [M + H]

Synthesis of4-bromo-5-((4-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methylthiazole

A solution of1-((4-bromo-2-methylthiazol-5-yl)methyl)-1H-pyrazole-4-carbaldehyde (580mg, 2.03 mmol) in DAST (5 mL) was stirred at 30° C. for 12 h under N₂.The reaction was quenched with sat. aq. NaHCO₃ (50 mL) at 0° C., andthen extracted with EtOAc (15 mL). The organic phase was dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (10→25% EtOAc in PE) to give4-bromo-5-((4-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methylthiazole(426 mg, 68% yield) as a yellow oil. LC/MS (ESI) (m/z): 308 [M+H]⁺.

Synthesis of 3,5-difluoro-2-iodobenzaldehyde

To a solution of 3,5-difluoro-2-iodo-N-methoxy-N-methylbenzamide (8.00g, 24.5 mmol) in THF (60 mL) at −78° C. was added dropwise DIBAL-H (36.7mL, 39.7 mmol, 1.0 M) under N₂ atmosphere. After the addition, themixture was stirred at 0° C. for 2 h. The mixture was quenched withice-water and then extracted with DCM (40 mL×2). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column chromatography onsilica gel (5% DCM in MeOH) to give 3,5-difluoro-2-iodobenzaldehyde (6.0g, 92%) as a yellow oil. LC-MS (ESI): m/z 269 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-(2-(3-bromo-5-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 393 [M + H]

Synthesis of [2-(1,3-dioxolan-2-yl)-4-fluorophenyl]trimethylstannane

To a mixture of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (1.0 g, 4.0mmol) in THF (20 mL) was added n-BuLi (1.78 mL, 4.45 mmol, 2.5 M)dropwise at −78° C. The mixture was stirred at −78° C. for 1 h. Then,trimethyltin chloride (4.45 mL, 4.45 mmol, 1.0 M in THE) was addeddropwise to the mixture. The resulting mixture was stirred at −78° C.for 15 min. The mixture was quenched with sat. NH₄Cl (50 mL) at 0° C.and extracted with EtOAc (50 mL×3). The combined extracts were washedwith brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicagel (10% EtOAc in PE) to give[2-(1,3-dioxolan-2-yl)-4-fluorophenyl]trimethylstannane (600 mg, yield:44%) as a colorless oil. LC/MS ESI (m/z): 333 [M+H]⁺.

Synthesis of(5-bromo-1-methyl-1H-pyrazol-4-yl)(5-iodo-1-methyl-1H-pyrazol-4-yl)methanol

To a solution of 5-bromo-4-iodo-1-methyl-1H-pyrazole (2.00 g, 6.99 mmol)in THF (35 mL) at −70° C. was added isopropylmagnesium bromide (1.0 M inTHF, 13.9 mL, 13.9 mmol) dropwise under an N₂ atmosphere. After theaddition, the mixture was stirred at −70° C. for 30 min, then a solutionof 5-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (2.14 g, 9.09 mmol) in THF(15 mL) was added dropwise at −70° C. over 10 min. The resulting mixturewas stirred at −70° C. for another 2 h before being quenched with sat.NH₄Cl solution (60 mL). The mixture was extracted with DCM (2×100 mL).The combined extracts were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography on silica gel (30% EtOAc in PE) to give(5-bromo-1-methyl-1H-pyrazol-4-yl)(5-iodo-1-methyl-1H-pyrazol-4-yl)methanolas a yellow oil (785 mg, yield: 29%). LC/MS ESI (m/z): 397 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(5-bromo-1-ethyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 411 [M + H]3-((4-chloropyridin-3-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 249 [M + H]

Synthesis of 1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-pyrazole

To a solution of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (3.0 g, 12.1mmol) in 1-methylpyrrolidine (50 mL), was added copper oxide (348 mg,2.43 mmol) at r.t., then followed by the addition of 1H-pyrazole (868mg, 12.8 mmol). After stirring at 120° C. overnight, the reactionmixture was diluted with EtOAc and water. The organic layer wasseparated, washed with sat. aq. NH₄Cl three times, brine once andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel (PE:EA=10:1 to 1:1, V/V) to give1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-pyrazole (2.0 g, 70% yield)as a yellow oil. TLC: R_(f)=0.3 (PE/EA=5:1), LC/MS ESI (m/z): 235[M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-3-methyl-1H-pyrazole

m/z (ESI): 249 [M + H]

Synthesis of5-fluoro-2-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)benzaldehyde

To a solution of (5-iodo-1-methyl-1H-pyrazol-4-yl)methanol (1.6 g, 6.7mmol) in dioxane (15 mL) and H₂O (5 mL) were added(4-fluoro-2-formylphenyl)boronic acid (1.69 g, 10.1 mmol), disodiumcarbonate (2.14 g, 20.2 mmol) and Pd(dppf)Cl₂ (492 mg, 0.670 mmol).After stirring at 80° C. for 2 h, the reaction was diluted with waterand extracted with EtOAc twice. The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography (silica gel, EtOAc/PE=1/1) to afford5-fluoro-2-[4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl]benzaldehyde (1.2g, 76% yield) as a white solid. LC/MS ESI (m/z): 235 [M+H]⁺.

Synthesis of3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

To a solution of1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (5.40 g,24.2 mmol) in THF (50 mL) was added LiTMP.MgCl₂ (1.0 M in THF, 36.3 mL,36.3 mmol) dropwise at −16° C. under nitrogen. The resulting solutionwas stirred at −16° C. for 1 h. N,N-dimethylformamide (3.7 mL, 48.4mmol) was then added and the mixture stirred for 1 h. The reaction wasquenched by the addition of brine, extracted with EtOAc (2×30 mL), driedand concentrated. The residue was purified by flash chromatography(silica gel, 0→5% ethyl acetate in petroleum ether) to afford3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile(3.4 g, 60%) as a brown liquid. LC/MS (ESI) m/z: 252 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

3-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

m/z (ESI): 460 [M + H]

Synthesis of(2-chloropyridin-3-yl)(3-ethyl-1-methyl-1H-pyrazol-5-yl)methanol

To a solution of 2-chloro-3-iodopyridine (1.04 g, 4.34 mmol) in THF (17mL) was added isopropylmagnesium bromide (5.21 mL, 3.43 mmol) at −5° C.After stirring at r.t. for 0.5 h,3-ethyl-1-methyl-1H-pyrazole-5-carbaldehyde (600 mg, 4.34 mmol) wasadded. Stirring was continued at r.t. for 0.5 h, then the mixture waspoured into water (80 mL) and extracted with EA (80 mL×3). The organiclayer was washed with sat. NaCl (60 mL×2), dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (30% EtOAc in PE) to afford(2-chloropyridin-3-yl)(3-ethyl-1-methyl-1H-pyrazol-5-yl)methanol (850mg, 78%) as a light-yellow solid. LC/MS (ESI): m/z=252 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 359 [M+H](1-(cyclopropylmethyl)-1H-pyrazol-4-yl)(1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methanol

m/z (ESI): 453 [M + H](5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 451 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(4-fluoro-2-iodophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol

m/z (ESI): 559 [M + H](3-chloro-1-ethyl-1H-pyrazol-4-yl)(1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methanol

m/z (ESI): 461 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)(3-chloro-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methanol

m/z (ESI): 355 [M + H](1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 401 [M + H](1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)(2,4-dibromothiazol-5-yl)methanol

m/z (ESI): 408 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)[3-chloro-1-(cyclopropylmethyl)-1H-pyrazol-4-yl]methanol

m/z (ESI): 345 [M + H](2-chloropyridin-3-yl)(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methanol

m/z (ESI): 264 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)[1-ethyl-3-(propan-2-yl)-1H-pyrazol-4-yl]methanol

m/z (ESI): 327 [M + H](1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)(1-(4-fluoro-2-iodophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol

m/z (ESI): 517 [M + H][1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl](3-iodo-1-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 373 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)(3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)methanol

m/z (ESI): 335 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)(3-(cyclopropylmethyl)-1-methyl-1H-pyrazol-5-yl)methanol

m/z (ESI): 325 [M + H]

Synthesis of2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)methyl)-5-methoxypyridine

To a solution of 3-(bromomethyl)-2-chloro-5-methoxypyridine (100 mg,0.423 mmol) in THF (2.5 mL) and H₂O (0.5 mL) was added(1-ethyl-1H-pyrazol-4-yl)boronic acid (59 mg, 0.42 mmol), K₃PO₄ (269 mg,1.27 mmol), and 1,1′-bis(di-t-butylphosphino)ferrocene palladiumdichloride (28 mg, 0.042 mmol). The mixture was stirred at 70° C. for 16h, then poured into water (80 mL) and extracted with EA (80 mL×3). Thecombined organic layers were washed with brine (60 mL), dried withNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography on silica gel (10→50% EtOAc in PE) to give2-chloro-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-methoxypyridine (100 mg,yield: 94%) as a white solid. LC/MS (ESI): m/z=252 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)methyl)-6-methoxypyridine

m/z (ESI): 252 [M + H]

Synthesis of2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)methyl)-4-methoxypyridine

To a solution of (2-chloro-4-methoxypyridin-3-yl)methanol (447 mg, 2.58mmol) in DCM (20 mL) were added CBr₄ (853 mg, 2.58 mmol) and PPh₃ (675mg, 2.58 mmol) at −10° C. The mixture was stirred at −10° C. for 2 h.The reaction was quenched with by sat. aq. NH₄Cl at 0° C. and extractedwith DCM (30 mL). The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by columnchromatography on silica gel (25 of EA in PE) to give3-(bromomethyl)-2-chloro-4-methoxypyridine (350 mg, yield: 58%) as ayellow oil. LC/MS (ESI) (m/z): 236 [M+H]⁺.

A mixture of 3-(bromomethyl)-2-chloro-4-methoxypyridine (250 mg, 1.06mmol), 1-ethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (234mg, 1.06 mmol), K₃PO₄ (179 mg, 0.846 mmol) and Pd(dppf)Cl₂ (28 mg, 0.042mmol) in water (1 mL) and THF (5 mL) was stirred at 95° C. under an N₂atmosphere for 4 h. The reaction mixture was filtered, and the filtratewas diluted with EA (50 mL). This solution was washed with brine (20mL), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by flash column chromatography (0→30 of EtOAc in PE) to give2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)methyl)-4-methoxypyridine (120 mg,yield: 45%) as a colorless oil. LC/MS (ESI) (m/z): 252 [M+H]⁺.

Synthesis of 4-bromo-5-((1-ethyl-1H-pyrazol-4-yl)methyl)oxazole

To a solution of (4-bromooxazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol(1.21 g, 4.45 mmol) in trifluoroacetic acid (12 mL), was addedtriethylsilane (3.60 mL, 22.2 mmol) and stirred at r.t. for 1.5 h. Thereaction mixture was then concentrated in vacuo to give a residue, whichwas diluted with EA (20 mL) and basified to pH 7 with sat. aq. NaHCO₃.The layers were separated, and the aq. phase was extracted with EA (3×20mL). The combined organic phases were washed with brine (10 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by flash chromatography (0→40% EtOAc in PE) to give4-bromo-5-((1-ethyl-1H-pyrazol-4-yl)methyl)oxazole (678 mg, 60% yield)as a yellow oil. LC/MS ESI (m/z): 256 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

ethyl5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole-3-carboxylate

m/z (ESI): 314 [M + H]3-(benzyloxy)-5-bromo-1-ethyl-4-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole

m/z (ESI): 501 [M + H]5-bromo-1-ethyl-4-((1-(4-fluoro-2-iodophenyl)-1H-imidazol-5-yl)methyl)-1H-pyrazole

m/z (ESI): 475 [M + H](R)-1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-3-(difluoromethyl)-5-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole

m/z (ESI): 455 [M + H]5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-3-(2,2-difluoroethyl)isoxazole

m/z (ESI): 306 [M + H]3-bromo-4-((1-ethyl-3-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole

m/z (ESI): 283 [M + H]4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-iodo-1,5-dimethyl-1H-pyrazole

m/z (ESI): 331 [M + H](R)-1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-methoxy-1H-pyrazole

m/z (ESI): 475 [M + H]5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-3-ethylisothiazole

m/z (ESI): 286 [M+H]3-iodo-1-methyl-4-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)methyl)-1H-pyrazole

m/z (ESI): 345 [M + H]3-bromo-1-ethyl-4-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole

m/z (ESI): 395 [M + H]3-bromo-4-((1-ethyl-1H-pyrazol-4-yl)methyl)-5-methoxy-1-methyl-1H-pyrazole

m/z (ESI): 299 [M + H]3-bromo-1-(tert-butyl)-4-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole

m/z (ESI): 311 [M + H]3-bromo-4-((1-isobutyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole

m/z (ESI): 297 [M + H]3-bromo-1-methyl-4-({1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}methyl)-1H-pyrazole

m/z (ESI): 309 [M + H]2,4-dibromo-5-{[1-(difluoromethyl)-1H-pyrazol-4-yl]methyl}-1,3-thiazole

m/z (ESI): 372 [M + H]5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-1-(4-fluoro-2-iodophenyl)-3-(trifluoromethyl)-1H-pyrazole

m/z (ESI): 501 [M + H]3-(2-bromo-4-fluorophenyl)-4-((1-ethyl-1H-pyrazol-4-yl)methyl)isoxazole

m/z (ESI): 350 [M + H]1-ethyl-4-{[3-(4-fluoro-2-iodophenyl)-1,2-thiazol-4-yl]methyl}-1H-1,2,3-triazole

m/z (ESI): 415 [M + H]1-(2-((benzyloxy)methyl)-4-fluorophenyl)-5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazole

m/z (ESI): 467 [M + H]1-(cyclopropylmethyl)-4-[(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl]-3-methyl-1H-pyrazole

m/z (ESI): 357 [M + H]1-(2-((benzyloxy)methyl)-4-fluorophenyl)-5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazole

m/z (ESI): 481 [M + H]1-(cyclopropylmethyl)-4-((1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-3-methyl-1H-pyrazole

m/z (ESI): 451 [M + H]2-chloro-3-[(3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl]pyridine

m/z (ESI): 236 [M + H]3-bromo-4-((5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-3-yl)methyl)-1-methyl-1H-pyrazole

m/z (ESI): 309 [M + H]

Synthesis of(3-bromo-1-methyl-1H-pyrazol-4-yl)(5-ethylisoxazol-3-yl)methanol

To a stirred solution of3-(3-bromo-1-methyl-1H-pyrazole-4-carbonyl)-5-ethyl-1,2-oxazole (400 mg,1.41 mmol) in methanol (10 mL) was added NaBH₄ (65 mg, 1.9 mmol) at 0°C. The reaction was stirred at 0° C. for 1 h, then concentrated todryness. The residue was purified by column chromatography on silica gel(PE:EtOAc=1:1, V/V) to give(3-bromo-1-methyl-1H-pyrazol-4-yl)(5-ethyl-1,2-oxazol-3-yl)methanol (360mg, 85% yield) as a white solid. LC/MS (ESI) (m/z): 286.0 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 418 [M + H]1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 461 [M + H]1-({1-[4-fluoro-2-(1-hydroxyethyl)phenyl]-1H-pyrazol-5-yl}methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 312 [M + H]1-({1-[4-fluoro-2-(1-hydroxyethyl)phenyl]-3-methyl-1H-pyrazol-5-yl}methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 326 [M + H](1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 565 [M + H]1-(2-(5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 419 [M + H]

Synthesis of5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-3-ethylisoxazole

To a solution of(3-bromo-1-methyl-H-pyrazol-4-yl)(3-ethylisoxazol-5-yl)methanol (900 mg,3.15 mmol) in dichloromethane (8 mL) were added triethylsilane (4.06 mL,25.2 mmol) and trifluoroacetic acid (2.34 mL, 31.5 mmol) at 0° C. Themixture was stirred at r.t. for 2 h. The solvent was removed in vacuumand the residue was treated with water and EA. The organic layer wasseparated and concentrated in vacuo to give5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-3-ethylisoxazole as a brownoil (680 mg, yield: 80%). LC/MS ESI (m/z): 270 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-bromo-1-ethyl-4-((5-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole

m/z (ESI): 395 [M + H]2-bromo-3-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)pyridine

m/z (ESI): 344 [M + H]5-bromo-4-((5-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole

m/z (ESI): 381 [M + H]5-bromo-1-cyclobutyl-4-((5-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole

m/z (ESI): 421 [M + H]5-chloro-4-((1-ethyl-1H-pyrazol-4-yl)methyl)-3-iodo-1-methyl-1H-pyrazole

m/z (ESI): 351 [M + H]5-bromo-1-ethyl-4-((1-(4-fluoro-2-iodophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazole

m/z (ESI): 543 [M + H]3-bromo-4-{[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]methyl}-1-ethyl-1H-pyrazole

m/z (ESI): 309 [M + H]3-bromo-4-((1,3-diethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole

m/z (ESI): 297 [M + H]5-bromo-3-(2-(5-((1-ethyl-1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluorobenzyloxy)-2-nitropyridine

m/z (ESI): 569 [M + H]5-bromo-3-{[2-(3-chloro-5-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-1H-pyrazol-1-yl)-5-fluorophenyl]methoxy}-2-nitropyridine

m/z (ESI): 562 [M + H]1-{2-[(1R)-1-(benzyloxy)ethyl]-4-fluorophenyl}-5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-methoxy-1H-pyrazolE

m/z (ESI): 435 [M + H]5-(2-bromo-4-fluorophenyl)-4-((1-ethyl-1H-pyrazol-4-yl)methyl)-3-methylisoxazole

m/z (ESI): 364 [M + H]5-bromo-4-((1-ethyl-5-iodo-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole

m/z (ESI): 395 [M + H]

Synthesis of (5-bromo-1-ethyl-1H-pyrazol-4-yl)(4-chloropyrimidin-5-yl)methanol

To a solution of 4-chloro-5-iodopyrimidine (2.60 g, 10.8 mmol) in THF(50 mL) at −78° C. was added n-BuLi (2.5 M in THF, 8.65 mL, 21.6 mmol)dropwise under N₂ atmosphere. The mixture was stirred at −78° C. for 10min, and then a solution of 5-bromo-1-ethyl-1H-pyrazole-4-carbaldehyde(1.98 g, 9.73 mmol) in THF (10 mL) was added dropwise at −78° C. Theresulting mixture was stirred at −78° C. for 30 min. The reaction wasquenched with sat. aq. NH₄Cl, then extracted with LA (100 ml×2). Theorganic layers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography (silicagel, 30% EtOAc in PE) to give(5-bromo-1-ethyl-1H-pyrazol-4-yl)(4-chloropyrimidin-5-yl)methanol as ayellow oil (1.4 g, yield: 41%). LC/MS ESI (m/z): 317 [M+H]⁺.

Synthesis of5-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

To a solution of 1-methyl-1H-pyrazole-3-carbonitrile (600 mg, 5.60 mmol)in THF (20 mL), was added lithium diisopropylamide (4.20 mL, 8.40 mmol,2.0 M in THF) dropwise at −78° C. for 1 h. After 1 h, a solution of3-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (1.98 g, 8.40 mmol) in THF(15 mL) was added dropwise and the resulting mixture was stirred at −78°C. for 2 h. The reaction mixture was quenched by adding sat. aq. NH₄Cl(20 mL), and then extracted with EA (3×20 mL). The combined organicphases were washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by flashchromatography with MeOH in DCM (0→5%, V/V) to give5-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(0.94 g, 82%) as a yellow solid. LC/MS ESI (m/z): 344 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carbonitrile

m/z (ESI): 516 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(4-bromopyridin-3-yl)methanol

m/z (ESI): 360 [M + H](1-(2-((1R)-1-(benzyloxy)ethyl)-4-fluorophenyl)-3-methoxy-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methanol

m/z (EST): 478 [M + H](dibromo-1,3-thiazol-5-yl)[1-(difluoromethyl)-1H-pyrazol-4-yl]methanol

m/z (EST): 388 [M + H]

Synthesis of3-cyclobutyl-5-((3-iodo-1-methyl-H-pyrazol-4-yl)methyl)isoxazole

A mixture of5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-3-cyclobutylisoxazole (230mg, 0.78 mmol), methyl[2-(methylamino)ethyl]amine (30 mg, 0.39 mmol) andCuI (40 mg, 0.21 mmol), KI (1.29 g, 7.79 mmol) in dioxane (5.0 mL) wasstirred at 100° C. for 5 h under N₂. The mixture was diluted with waterand extracted with EA (50 mL×3). The combined extracts were washed withbrine twice, dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography (0→50% EA in PE) to give3-cyclobutyl-5-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole (220mg, 78% yield) as a yellow oil. LC-MS(ESI): 344 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

3-ethyl-5-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole

m/z (ESI): 318 [M + H]5-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole-3-carbonitrile

m/z (ESI): 315 [M + H]3-(2,2-difluoroethyl)-5-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole

m/z (ESI): 354 [M + H]

Synthesis of tert-butyl2-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)hydrazine-1-carboxylate

A solution of 3-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (4.70 g, 19.9mmol) and tert-butyl carbazate (2.63 g, 19.9 mmol) in MeOH (20 mL) wasstirred at 25° C. for 12 h. The mixture was concentrated under reducedpressure to give crude tert-butyl(E)-2-((3-iodo-1-methyl-1H-pyrazol-4-yl)methylene)hydrazine-1-carboxylate(6.80 g, 98% yield) as a yellow oil. LC/MS ESI (m/z): 351 [M+H]⁺.

To a solution of tert-butyl(E)-2-((3-iodo-1-methyl-1H-pyrazol-4-yl)methylene)hydrazine-1-carboxylate(6.80 g, 19.4 mmol) in AcOH (20 mL) was added NaBH₃CN (1.22 g, 19.4mmol) at 0° C. The reaction mixture was stirred for 12 h at 25° C. Themixture was concentrated under reduced pressure. The residue wasdissolved in EtOAc (20 mL), washed with sat. Na₂CO₃ (20 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (10→30% EA in PE) togive tert-butyl2-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)hydrazine-1-carboxylate (5.00g, 73% yield) as a white solid. LC/MS ESI (m/z): 353 [M+H]⁺.

Synthesis of5-chloro-3-iodo-(1-methyl-1H-pyrazol-4-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

Isopropylmagnesium chloride-lithium chloride complex (1.88 mL, 2.45mmol, 1.3 M in THF) was added to the solution of1-ethyl-4-iodo-1H-pyrazole (502 mg, 2.26 mmol) dropwise in THF (4 mL) at0° C. under N₂. The mixture was stirred for 1 h and then5-chloro-3-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (510 mg, 1.89 mmol)in THF (1 mL) was added to the mixture dropwise at 0° C. The mixture waswarmed to r.t. and stirred for 2 h under N₂. The reaction mixture waspoured into water (100 mL) and then extracted with EA (100 mL×2). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by columnchromatography (silica gel, 1-10% EA in PE) to afford5-chloro-3-iodo-(1-methyl-1H-pyrazol-4-yl)(1-ethyl-1H-pyrazol-4-yl)methanol(420 mg, 61%) as a yellow solid. LC/MS (ESI) m/z: 367 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(3-bromo-1-ethyl-1H-pyrazol-4-yl)[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]methanol

m/z (ESI): 325 [M + H](1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)(1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methanol

m/z (ESI): 467 [M + H]

Synthesis of(2,4-dibromothiazol-5-yl)(3-ethyl-1-methyl-1H-pyrazol-5-yl)methanol

To a stirred solution of 3-ethyl-5-iodo-1-methyl-1H-pyrazole (1.40 g,5.93 mmol) in THF (20 mL) was added i-PrMgCl.LiCl (4.6 mL, 1.3 M in THF,5.93 mmol) dropwise at 0° C. under N₂. After stirring at 0° C. for 1 h,a solution of 2,4-dibromothiazole-5-carbaldehyde (1.77 g, 6.52 mmol) inTHF (5 mL) was added at 0° C. The reaction was stirred at 0° C. for 2 hand LCMS showed the reaction was complete. The reaction was quenchedwith sat. NH₄Cl (15 mL), extracted with EtOAc (10 mL), dried overanhydrous Na₂SO₄ and concentrated to dryness. The residue was purifiedby column chromatography on silica gel (PE:EtOAc=1:1) to give(2,4-dibromothiazol-5-yl)(3-ethyl-1-methyl-1H-pyrazol-5-yl)methanol(1.10 g, 49% yield) as a yellow oil. LC/MS (ESI) (m/z): 379.9 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(3-iodo-1-methyl-1H-pyrazol-4-yl)(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)methanol

m/z (ESI): 387 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)(3-(2,2-difluoroethyl)isoxazol-5-yl)methanol

m/z (ESI): 322 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)[1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl]methanol

m/z (ESI): 335 [M + H][3-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl](1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 321 [M + H](3-iodo-1-methyl-1H-pyrazol-4-yl)(1-(oxetan-3-yl)-1H-pyrazol-4-yl)methanol

m/z (ESI): 361 [M + H](3-bromo-5-methoxy-1-methyl-1H-pyrazol-4-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 315 [M + H](3-bromo-1-methyl-1H-pyrazol-4-yl)({1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl})methanol

m/z (ESI): 325 [M + H]4-((3-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 310 [M + H][3-(2-bromo-4-fluorophenyl)-1,2-oxazol-4-yl](1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 366 [M + H](5-(2-bromo-4-fluorophenyl)-3-methylisoxazol-4-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 380 [M + H]

Synthesis of1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-4-fluoro-1H-pyrazole

To a solution of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (4.62 g, 18.7mmol) in DMF (20 mL) at r.t. was added 4-fluoro-1H-pyrazole (1.77 g,20.6 mmol), cesium carbonate (9.14 g, 28.1 mmol), CuI (0.71 g, 3.7 mmol)and L-proline (0.43 g, 3.4 mmol). The mixture was degassed under N₂ forthree times and stirred at 120° C. overnight. After cooling to r.t., thereaction mixture was filtered, the filtrate was diluted with sat. aq.NH₄Cl (50 mL) and extracted with EtOAc (3×50 mL). Then the combinedorganic extracts were washed with sat. aq. NH₄Cl (3×30 mL) and brine (30mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. Theresidue was purified by flash chromatography (silica gel, 0→10% EtOAc inPE) to give1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-4-fluoro-1H-pyrazole as a brownoil (2.62 g, yield: 56%). LC/MS (ESI) m/z: 253 [M+H]⁺.

Synthesis of1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-3-fluoro-1H-pyrazole

To a solution of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (1.37 g, 5.54mmol) in 1-methyl-2-pyrrolidinone (5 mL) was added 3-fluoro-1H-pyrazole(0.53 g, 6.1 mmol), cesium carbonate (2.71 g, 8.32 mmol) and cuprousoxide (0.16 g, 1.1 mmol), the resulting mixture was stirred at 120° C.overnight. The reaction mixture was cooled to r.t., diluted with EA (5mL) and sat. aq. NH₄Cl solution (5 mL). The layers were separated, andthe aq. phase was extracted with EA (3×5 mL). The combined organicphases were washed with sat. aq. NH₄Cl (5 mL) and brine (5 mL), driedover anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residuewas purified by flash chromatography (0→10% EA in PE) to give1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-3-fluoro-1H-pyrazole (486 mg,35%) as a light-yellow oil. LC/MS ESI (m/z): 253 [M+H]⁺.

Synthesis of(Z)-4-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-2-((dimethylamino)methylene)-3-oxobutanenitrile

To a mixture of 2-(5-bromo-1-ethyl-1H-pyrazol-4-yl)acetonitrile (4.50 g,21.0 mmol) and MeOH (50 mL) was added cone. H₂SO₄ (10 mL) dropwise at25° C. After stirring at 80° C. for 16 h, the mixture was slowlyneutralized to pH 8 with sat. NaHCO₃ at 0° C. The resulting mixture wasextracted with EtOAc twice. The combined extracts were washed with H₂Oand brine, dried over anhydrous Na₂SO₄, filtered, and concentrated undervacuum. The residue was purified by column chromatography on silica gel(0→20% EA in PE) to give methyl2-(5-bromo-1-ethyl-1H-pyrazol-4-yl)acetate (3.3 g, yield: 64%) as ayellow oil. LC/MS ESI (m/z): 247 [M+H]⁺.

To a solution of potassium 2-methylbutan-2-olate (10.0 mL, 20.0 mmol, 2M in THF) in dry THF (50 mL) was added acetonitrile (822 mg, 20.0 mmol)and methyl 2-(5-bromo-1-ethyl-1H-pyrazol-4-yl)acetate (3.30 g, 13.4mmol) at 0° C. After stirring at 25° C. for 16 h, the mixture wasfiltered, and the filter cake was collected and rinsed with hexane. Thefilter cake was dissolved in water and adjusted to pH 3 with aq. HCl (1N). The resulting mixture was then extracted with EtOAc twice. Thecombined organic extracts were washed with H₂O and brine, dried overanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby column chromatography on silica gel to give4-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-3-oxobutanenitrile (1.9 g, yield:56%) as a brown oil. LC/MS ESI (m/z): 256 [M+H]⁺.

To a solution of 4-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-3-oxobutanenitrile(1.6 g, 6.3 mmol) in THF (20 mL) was added DMF-DMA (1.50 g, 12.5 mmol)at 25° C. After stirring at 25° C. for 2 h, the reaction mixture wasdiluted with EtOAc, washed with H₂O and brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography on silica gel to give(Z)-4-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-2-((dimethylamino)methylene)-3-oxobutanenitrile(1.1 g, yield: 56%) as a yellow solid. LC/MS (ESI) m/z: 311 [M+H]⁺.

Synthesis of3-((2-chloropyridin-3-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

A mixture of4-bromo-3-[(2-chloropyridin-3-yl)methyl]-1-methyl-1H-pyrazole-5-carbonitrile(270 mg, 0.87 mmol), PPh₃ (46 mg, 0.17 mmol), K₂CO₃ (240 mg, 1.73 mmol)and Pd(OAc)₂ (20 mg, 0.087 mmol) in n-BuOH (20 mL) was stirred at 80° C.under N₂ overnight. After cooling to r.t., the mixture was filtered andthe filtrate was concentrated. The residue was treated with water andextracted with EA (2×100 mL). The combined organic extracts were washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby flash column chromatography on silica gel (PE:EA=5:1) to give3-((2-chloropyridin-3-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile (70mg, 31%) as a colorless oil. LC/MS (ESI): m/z=233 [M+H]⁺.

Synthesis of ethyl 3-(2-bromo-4-fluorophenyl)-1,2-oxazole-4-carboxylate

To a solution of 2-bromo-4-fluorobenzaldehyde (5.9 mL, 49 mmol) andhydroxylamine hydrochloride (10.0 g, 145 mmol) in EtOH (120 mL) andwater (120 mL) was added sodium hydroxide (4.40 g, 110 mmol). Themixture was stirred at r.t. overnight. The reaction mixture wasacidified with 1 N HCl to pH 5, then concentrated to remove EtOH. Theresidue was dissolved in EtOAc (120 mL), washed with brine (120 mL),dried over Na₂SO₄, filtered, and concentrated to dryness. The residuewas purified by column chromatography on silica gel (PE:EA=5:1) to giveN-[(2-bromo-4-fluorophenyl)methylidene]hydroxylamine (10.74 g, 100%yield) as a white solid. LC/MS (ESI) m/z: 218 [M+H]⁺.

To a solution of N-[(2-bromo-4-fluorophenyl)methylidene]hydroxylamine(10.74 g, 49.25 mmol) in N,N-dimethylformamide (50 mL) was added NCS(8.55 g, 64.0 mmol) at 0° C. After stirring at r.t. for 2 h, thereaction was concentrated. The residue was diluted with EtOAc (50 mL),washed with sat. NaHCO₃ (50 mL) and brine (50 mL), dried over Na₂SO₄,filtered, and concentrated to give crude(Z)-2-bromo-4-fluoro-N-hydroxybenzimidoyl chloride (12.44 g, 100% yield)as a yellow oil. LC/MS (ESI) m/z: 252 [M+H]⁺.

To a solution of 2-bromo-4-fluoro-N-hydroxybenzimidoyl chloride (5.0 g,20 mmol) and ethyl prop-2-ynoate (1.94 g, 19.8 mmol) in toluene (50 mL)was added TEA (6.00 g, 59.4 mmol). The mixture was stirred at 50° C.overnight, and then the reaction was concentrated. The residue wasdiluted with EtOAc (50 mL), washed with brine (50 mL), dried overNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby column chromatography on silica gel (PE:EtOAc=5:1) to give ethyl3-(2-bromo-4-fluorophenyl)isoxazole-4-carboxylate (as a mixturecontaining both regioisomers, 4.62 g, 74% yield) as a yellow oil. LC/MS(ESI) m/z: 314 [M+H]⁺.

Synthesis of methyl5-(2-bromo-4-fluorophenyl)-3-methyl-1,2-oxazole-4-carboxylate

To a stirred solution of methyl 3-oxobutanoate (20.0 g, 172 mmol) inMeOH (20 mL) was added methanamine (17.4 g, 224 mmol, 40% in water). Thereaction was stirred at r.t. overnight. The reaction was concentratedunder reduced pressure to give crude methyl(2E)-3-(methylamino)but-2-enoate (18.0 g, 81% yield) as a colorless oil.LC/MS (ESI) m/z: 130 [M+H]⁺.

To a solution of 2-bromo-4-fluorobenzoic acid (2.0 g, 9.1 mmol) in SOCl₂(10 mL) was added DMF (0.07 mL) dropwise at 0° C. The reaction wasstirred for 1 h at 80° C. The reaction was cooled to r.t. andconcentrated under reduced pressure to give crude2-bromo-4-fluorobenzoyl chloride (2.0 g, 92% yield) as a colorless oil.

To a solution of methyl (2E)-3-(methylamino)but-2-enoate (1.0 g, 7.7mmol) in THF (10 mL) was added pyridine (0.94 mL, 12 mmol) and2-bromo-4-fluorobenzoyl chloride (1.80 g, 7.74 mmol). The reactionmixture was stirred overnight at 20° C. and then concentrated underreduced pressure. The residue was purified by flash columnchromatography (0→30% EA in PE) to give methyl(3E)-2-(2-bromo-4-fluorobenzoyl)-3-(methylimino)butanoate (0.40 g, 16%yield) as a colorless oil. LC/MS (ESI) m/z: 330 [M+H]⁺.

A mixture of methyl(3E)-2-(2-bromo-4-fluorobenzoyl)-3-(methylimino)butanoate (400 mg, 1.21mmol) and hydroxylamine hydrochloride (126 mg, 1.82 mmol) in AcOH (5 mL)was stirred at 110° C. for 1 h. The reaction mixture was cooled to r.t.and concentrated under reduced pressure. The residue was purified byflash column chromatography (0→20% EA in PE) to give methyl5-(2-bromo-4-fluorophenyl)-3-methyl-1,2-oxazole-4-carboxylate (300 mg,79% yield) as a colorless oil. LC/MS (ESI): m/z=314 [M+H]⁺.

Synthesis of 5,7-difluoro-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of 1-(3,5-difluoro-2-iodophenyl)ethan-1-ol (1.00 g, 3.52mmol) in THF (30 mL) at −40° C. was added i-PrMgBr (6.8 mL, 6.8 mmol, 1M) dropwise under an N₂ atmosphere. After the addition, the mixture wasstirred at −10° C. for 0.5 h, then a solution of trimethyl borate (1.0 Min THF, 8.8 mL, 8.8 mmol) was added at −10° C. The resulting mixture wasstirred at r.t. for 16 h. The mixture was quenched with ice-water andthen extracted with EA (100 mL×2). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column chromatography onsilica gel (PE:EA=2:1) to give5,7-difluoro-3-methyl-1,3-dihydro-2,1-benzoxaborol-1-ol (700 mg, 95%) asa colorless oil. LC-MS (ESI): m/z 185 [M+H]⁺.

Synthesis of ethyl 3-(2-bromo-4-fluorophenyl)isothiazole-4-carboxylate

Ethyl prop-2-ynoate (3.48 g, 35.5 mmol) was dropwise added to a solutionof 5-(2-bromo-4-fluorophenyl)-2H-1,3,4-oxathiazol-2-one (4.90 g, 17.8mmol) in toluene (50 mL) at r.t. The reaction was stirred for 16 h at120° C., concentrated in vacuo, and the residue was purified by flashchromatography (0→30% EA in PE) to give ethyl3-(2-bromo-4-fluorophenyl)isothiazole-4-carboxylate (1.7 g, 29% yield)as a white solid. LC/MS (ESI) m/z: 330 [M+H]⁺.

Synthesis of ethyl 1-(4-fluoro-2-iodophenyl)-1H-imidazole-5-carboxylate

To a solution of 4-fluoro-2-iodoaniline (10.00 g, 42.19 mmol) in MeOH(100 mL) was added ethyl 2-oxoacetate (10.01 mL, 50.63 mmol, 50% intoluene) and the resulting mixture was heated at reflux for 3.5 h. Themixture was concentrated in vacuo and the resulting residue wasdissolved in anhydrous ethanol (100 mL) and treated with1-isocyanomethanesulfonyl-4-methylbenzene (12.35 g, 63.28 mmol) andK₂CO₃ (11.66 g, 84.38 mmol). The resulting mixture was heated to 65° C.and stirred for 4 h, then cooled to r.t. and poured into water andEtOAc. The organic layer was separated, concentrated under reducedpressure, and purified by flash chromatography on silica gel (0→30%EtOAc in PE) to give ethyl1-(4-fluoro-2-iodophenyl)-1H-imidazole-5-carboxylate (11 g, 72% yield)as a yellow solid. LC/MS (ES+): m/z=361 [M+H]⁺.

Synthesis of1-(4-fluoro-2-iodophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine

To a solution of 4,4,4-trifluoro-3-oxobutanenitrile (4.00 g, 29.2 mmol)and (4-fluoro-2-iodophenyl)hydrazine hydrochloride (10.1 g, 35.0 mmol)in EtOH (100 mL) was added conc. HCl (10 mL) dropwise at 25° C. Afterbeing stirred at 80° C. for 16 h, the reaction was neutralized to pH 8with NaHCO₃ and then diluted with EtOAc. The resulting mixture waswashed with H₂O and brine. The organic layer was dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under vacuum.The residue was purified by silica gel column chromatography, elutedwith PE/EA (0→17%) to give1-(4-fluoro-2-iodophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (5 g,38% yield) as a brown solid. LC/MS ESI (m/z): 372 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

ethyl5-amino-4-ethyl-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carboxylate

m/z (ESI): 404 [M + H]

Synthesis of ethyl 3-(4-fluoro-2-iodophenyl)isothiazole-4-carboxylate

To a solution of 5-(4-fluoro-2-iodophenyl)-2H-1,3,4-oxathiazol-2-one(2.80 g, 8.66 mmol) in toluene (30 mL) was added ethyl prop-2-ynoate(1.76 mL, 17.3 mmol). The resulting solution was stirred at 120° C. in asealed tube for 16 h. The mixture was concentrated under vacuum and theresidue was purified by flash chromatography on silica gel (EA/PE=1/5)to give ethyl 3-(4-fluoro-2-iodophenyl)-1,2-thiazole-4-carboxylate (650mg, 20%) as a colorless oil. LC/MS (ESI): m/z=378 [M+H]⁺.

Synthesis of2-chloro-3-((4-(cyclopropylmethyl)-1H-pyrazol-1-yl)methyl)pyridine

To a solution of(1-((2-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)(cyclopropyl)methanol(400 mg, 1.5 mmol) in TFA (2 mL) was added triethylsilane (2.4 mL, 15.1mmol). The resulting mixture was stirred at 60° C. for 2 h. The reactionmixture was cooled down to r.t. and concentrated under reduced pressure.The residue was basified with sat. aq. NaHCO₃ solution to pH 7 andextracted with DCM (2×10 ml). The combined organic layers were washedwith brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column chromatography onsilica gel (PE:EtOAc=1:1, V/V) to give2-chloro-3-((4-(cyclopropylmethyl)-1H-pyrazol-1-yl)methyl)pyridine (250mg, 67%) as a yellow oil. LC/MS (ESI) (m/z): 248 [M+H]⁺.

Synthesis of5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-4-chloropyrimidine

To a solution of5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)pyrimidin-4-ol (970 mg, 3.43mmol) in MeCN (30 mL) at 0° C. was added POCl₃ (1.58 g, 10.3 mmol)dropwise under N₂ atmosphere. After the addition, the mixture wasstirred at 80° C. for 3 h. The reaction mixture was quenched with sat.NaHCO₃ and extracted with DCM (100 ml×2). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel (30% EtOAc in PE) to give5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-4-chloropyrimidine as ayellow solid (587 mg, yield: 57%). LC/MS ESI (m/z): 301 [M+H]⁺.

Synthesis of(3-bromo-1-(tert-butyl)-1H-pyrazol-4-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

n-BuLi (1.30 mL, 3.25 mmol, 2.5 M in THF) was added slowly to a solutionof 1-ethyl-4-iodo-1H-pyrazole (961 mg, 4.33 mmol) in THF (10 mL) at −78°C. and the reaction mixture was stirred for 40 min at −78° C.(additional equivalents of base can be used in cases where substratescontain additional acidic protons). Then3-bromo-1-(tert-butyl)-1H-pyrazole-4-carbaldehyde (500 mg, 2.16 mmol) inTHF (5 mL) was dropwise added at −78° C. and the reaction mixture wasstirred for 0.5 h at −78° C. This reaction was quenched with sat. NH₄Cl(10 mL) and extracted with EtOAc (20 mL×2). The combined organic phaseswere washed with brine (20 mL), dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by flash column chromatography onsilica gel (PE:EtOAc=1:1) to give(3-bromo-1-(tert-butyl)-1H-pyrazol-4-yl)(1-ethyl-1H-pyrazol-4-yl)methanol(283 mg, 40% yield) as a yellow oil. LC/MS ESI (m/z): 327 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-pyrazol-5-yl)(5-bromo-1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 437 [M + H](1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-4-fluoro-1H-pyrazol-5-yl)(5-bromo-1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 455 [M + H](1-(2-((R)-1-(benzyloxy)ethyl)-4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 471 [M + H](1-(2-((R)-1-(benzyloxy)ethyl)-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methanol

m/z (ESI): 515 [M + H](1-ethyl-1H-1,2,3-triazol-4-yl)(1-(4-fluoro-2-((R)-1-(4-methoxybenzyloxy)ethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol

m/z (ESI): 520 [M + H]5-((3-chloro-1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 496 [M+H]5-((1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 530 [M + H](1-(2-((R)-1-(benzyloxy)ethyl)-4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methanol

m/z (ESI): 498 [M + H]5-((3-(difluoromethyl)-1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 512 [M + H]4-((2-chloropyridin-3-yl)(hydroxy)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile

m/z (ESI): 289 [M + H](1-(2-((R)-1-(benzyloxy)ethyl)-4-fluorophenyl)-3-methoxy-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 491 [M + H](1-(2-((R)-1-(benzyloxy)ethyl)-4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 511 [M + H](1-(2-((R)-1-(benzyloxy)ethyl)-4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methanol

m/z (ESI): 497 [M + H][1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl](1-{4-fluoro-2-[(1R)-1-[(4-methoxyphenyl)methoxy]ethyl]phenyl}-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol

m/z (ESI): 546 [M + H](1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 373 [M + H](1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-3-fluoro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 377 [M + H](3-chloro-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 351 [M + H](3-chloro-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methanol

m/z (ESI): 378 [M+H](1-(2-((R)-1-(benzyloxy)ethyl)-4-fluorophenyl)-3-methoxy-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 451 [M + H]5-((3-chloro-1-(4-fluoro-2-(((4-methoxybenzyl)oxy)methyl)phenyl)-1H-pyrazol-5-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 482 [M + H](1-(2-((benzyloxy)methyl)-4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methanol

m/z (ESI): 483 [M + H](1-(2-((benzyloxy)methyl)-4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 497 [M + H]5-((1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-pyrazol-5-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbaldehyde

m/z (ESI): 489 [M + H]

Synthesis of 4-(hydrazinylmethyl)-3-iodo-1-methyl-1H-pyrazolehydrochloride

To a solution of tert-butyl2-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)hydrazine-1-carboxylate (5.00g, 14.2 mmol) in MeOH (20 mL) was added HCl (30 mL, 4 N in dioxane) atr.t. The mixture was stirred for 12 hi at 25° C., and then concentratedunder reduced pressure to give4-(hydrazinylmethyl)-3-iodo-1-methyl-1H-pyrazole hydrochloride (3.30 g,75% yield) as a white solid. LC/MS ESI (m/z): 253 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

4-fluoro-2-iodobenzohydrazide

m/z (ESI): 281 [M + H]

Synthesis of (R)-1-(5-fluoro-2-iodophenyl)ethyl benzoate

To a mixture of (1S)-1-(5-fluoro-2-iodophenyl)ethan-1-ol (1.00 g, 3.76mmol), benzoic acid (0.550 g, 4.51 mmol) and triphenylphosphine (1.18 g,4.51 mmol) in THF (30 mL) was added DIAD (0.89 mL, 4.5 mmol) dropwise at0° C. under N₂. The resulting mixture was stirred at r.t. overnight,poured into water, and then extracted with EtOAc (50 mL×2). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography (silicagel, 1→5% ethyl acetate in petroleum ether) to afford(1R)-1-(5-fluoro-2-iodophenyl)ethyl benzoate (1.2 g, 86%) as a yellowsolid. LC/MS (ESI): m/z=371 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(R)-3-(1-(5-fluoro-2-iodophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 389 [M + H]

Synthesis of tert-butyl2-(4-fluoro-2-iodobenzoyl)hydrazine-1-carboxylate

To a solution of 4-fluoro-2-iodobenzoic acid (8.50 g, 32.0 mmol) in DCM(50 mL) were added EDCI (6.14 g, 32.0 mmol), HOBT (4.32 g, 3.02 mmol)and TEA (6.46 g, 64.0 mmol). The mixture was stirred at r.t. for 0.5 h.Then tert-butyl hydrazinecarboxylate (5.07 g, 38.3 mmol) was added. Thereaction mixture was stirred at r.t. for 16 h, quenched with water andextracted with EA (100 mL). The organic layer was concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (0→30% EA in PE) to give tert-butyl2-(4-fluoro-2-iodobenzoyl)hydrazine-1-carboxylate (7.6 g, 63%) as awhite solid. LC/MS (ESI): m/z=381 [M+H]⁺.

Synthesis of5-bromo-1-(cyclopropylmethyl)-4-[(2-iodo-4-methyl-1H-imidazol-1-yl)methyl]-3-methyl-1H-pyrazole

To a solution of5-bromo-4-(chloromethyl)-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole (639mg, 2.42 mmol) and 2-iodo-4-methyl-1H-imidazole (420 mg, 2.02 mmol) inDMF (5 mL) was added K₂CO₃ (1.12 g, 8.08 mmol). This mixture was stirredat 25° C. for 16 h. The reaction was concentrated, and the residue wasdiluted with EtOAc (45 mL). The mixture was washed with brine (15 mL),dried over Na₂SO₄, and then concentrated. The residue was purified byflash column chromatography (silica gel, 30→85% EtOAc in PE) to give5-bromo-1-(cyclopropylmethyl)-4-[(2-iodo-4-methyl-1H-imidazol-1-yl)methyl]-3-methyl-1H-pyrazole(500 mg, yield: 57%) as a light-yellow solid. LC-MS (ESI) m/z: 435[M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-bromo-1-ethyl-4-((2-(4-fluoro-2-iodophenyl)-4-methyl-1H-imidazol-1-yl)methyl)-1H-pyrazole

m/z (ESI): 489 [M + H]2-(1-((5-bromo-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorobenzaldehyde

m/z (ESI): 413 [M + H]2-(1-{[5-bromo-1-(2-fluoroethyl)-1H-pyrazol-4-yl]methyl}-1H-imidazol-2-yl)-5-fluorobenzaldehyde

m/z (ESI): 395 [M + H]2-(1-((5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorobenzaldehyde

m/z (ESI): 399 [M + H]

Synthesis of ethyl3-bromo-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-5-carboxylate

To a solution of (4-fluoro-2-iodophenyl)hydrazine hydrochloride (600 mg,2.08 mmol) in H₂O (10 mL) was added conc. HCl (257 mg, 2.50 mmol),followed by the addition of a 50% aq. solution of 2-oxoacetic acid (339mg, 2.29 mmol) dropwise at 15° C. The resulting mixture was stirred at15° C. for 0.5 h. The resulting precipitate was collected by filtration,washed with H₂O, and dried in vacuo to give crude(2E)-2-[2-(4-fluoro-2-iodophenyl)hydrazin-1-ylidene]acetic acid (500 mg,78%) as a pale-yellow solid. LC/MS (ESI) m/z: 309 [M+H]⁺.

To a solution of (E)-2-(2-(4-fluoro-2-iodophenyl)hydrazono)acetic acid(4.50 g, 14.6 mmol) in DMF (30 mL) was added NBS (5.20 g, 29.2 mmol) at−10° C. and the mixture was stirred −10° C. for 30 min. The reaction wasfiltered and concentrated in vacuo. The residue was purified by flashchromatography (0-5% EtOAc in PE) to give(dibromomethyl)(4-fluoro-2-iodophenyl)diazene (1.78 g, 27% yield) as anoff-white solid. LC/MS (ESI) m/z: 421 [M+H]⁺.

To a solution of (dibromomethyl)(4-fluoro-2-iodophenyl)diazene (1.76 g,4.17 mmol) and TEA (1.26 g, 12.5 mmol) in DMF (30 mL) was added asolution of ethyl propiolate (0.75 mL, 4.5 mmol) in DCM (2 mL) dropwiseat −10° C. The reaction was stirred at −10° C. for 10 min, and thenfiltered and concentrated in vacuo. The residue was purified by flashchromatography (0→20% EtOAc in PE) to give ethyl3-bromo-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-5-carboxylate (1.2 g, 62%yield) as an off-white solid. LC-MS(ESI): 439 [M+H]⁺.

Synthesis of1-(4-fluoro-2-iodophenyl)-5-iodo-3-(trifluoromethyl)-1H-pyrazole

To a mixture of KI (6.70 g, 40.4 mmol) and isopentyl nitrite (4.70 g,40.4 mmol) in THF (100 mL) was added a solution of1-(4-fluoro-2-iodophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (5.00g, 13.4 mmol) in THF (80 mL) dropwise at 0° C. After stirring at 85° C.for 16 h, the reaction was diluted with EtOAc. The resulting mixture waswashed with H₂O and brine. The organic layer was dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under vacuum.The residue was purified by silica gel column chromatography (0-A40%EtOAc in PE) to give1-(4-fluoro-2-iodophenyl)-5-iodo-3-(trifluoromethyl)-1H-pyrazole (3.7 g,57% yield) as a clear oil. LC/MS ESI (m/z): 483 [M+H]⁺.

Synthesis of (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of (1R)-1-(5-fluoro-2-iodophenyl)ethyl benzoate (300 mg,0.81 mmol) in methanol (8 mL) was added a solution of NaOH (32 mg, 0.81mmol) in water (8 mL). The mixture was stirred at r.t. overnight. Thereaction mixture was poured into water and then extracted with EtOAc (50mL×2). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by columnchromatography (silica gel, 1→5% ethyl acetate in petroleum ether) toafford (1R)-1-(5-fluoro-2-iodophenyl)ethan-1-ol (150 mg, 70%) as a whitesolid. LC/MS (ESI): m/z=267 [M+H]⁺.

Isopropylmagnesium chloride-lithium chloride complex, 1.3M solution inTHF (72.3 mL, 94.0 mmol) was added to the mixture of(1R)-1-(5-fluoro-2-iodophenyl)ethan-1-ol (10.00 g, 37.59 mmol) in THF(120 mL) at −40° C. under N₂ dropwise. The mixture was stirred at −40°C. under N₂ for 1 h, then warmed to −10° C. for another 0.5 h beforetrimethyl borate (10.67 mL, 93.97 mmol) was added dropwise over 10 minat −10° C. After stirring at r.t. overnight under N₂, The reactionmixture was poured into sat. NH₄Cl solution (100 mL) and then extractedwith EtOAc (50 mL×2).

The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by columnchromatography (silica gel, 1→10% ethyl acetate in petroleum ether) toafford (R)-5-fluoro-3-methylbenzo[c] [1,2] oxaborol-1(3H)-ol (4.0 g,64%) as a colorless oil. LC/MS (ESI): m/z=167 [M+H]⁺.

Synthesis of 3-(4-fluoro-2-iodophenyl)-1,2-thiazole-4-carbaldehyde

To a solution of [3-(4-fluoro-2-iodophenyl)-1,2-thiazol-4-yl]methanol(550 mg, 1.64 mmol) in DCM (20 mL), was added MnO₂ (1.42 g, 16.4 mmol)at r.t. Then this mixture was stirred at 40° C. for 32 h. The reactionmixture was filtered, and the filtrate was concentrated. The residue waspurified by column chromatography on silica gel (30% EtOAc in PE) toafford 3-(4-fluoro-2-iodophenyl)-1,2-thiazole-4-carbaldehyde (400 mg,73%) as a light-yellow solid. LC/MS (ESI): m/z=334 [M+H]⁺.

Synthesis of 3-(1-(5-fluoro-2-iodophenyl)ethoxy)-2-nitropyridine

To a solution of 1-(5-fluoro-2-iodophenyl)ethan-1-ol (9.20 g, 34.6 mmol)in THF (180 mL) at 0° C. was added portion-wise NaH (1.38 g, 34.6 mmol,60% in mineral oil) over 10 min. After the addition, the mixture wasstirred at 0° C. for 15 min, and then a solution of3-fluoro-2-nitropyridine (4.91 g, 34.6 mmol) in THF (20 mL) was addeddropwise. The ice bath was removed, and the mixture was stirred at r.t.for 3 h. The reaction mixture was partitioned between DCM (200 mL) andwater (200 mL). The organic layer was separated, washed with brine, andconcentrated in vacuo. The residue was purified by flash chromatography(eluent: 0→30% EtOAc in PE) to give3-(1-(5-fluoro-2-iodophenyl)ethoxy)-2-nitropyridine (5.3 g, yield: 39%)as a white solid. LC/MS ESI (m/z): 389 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(R)-3-chloro-1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazole

m/z (ESI): 361 [M + H](R)-1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazole

m/z (ESI): 327 [M + H](R)-1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-3-methoxy-1H-pyrazole

m/z (ESI): 327 [M + H](R)-3-(1-(2-(4-((3-(benzyloxy)-5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-5-bromo-2-nitropyridine

m/z (ESI): 713 [M + H](R)-5-bromo-3-(1-(2-(4-((5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 647 [M + H]5-bromo-3-[(1R)-1-[2-(1-{[5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl]methyl}-4-methyl-1H-imidazol-2-yl)-5-fluorophenyl]ethoxy]-2-nitropyridine

m/z (ESI): 647 [M + H]5-bromo-3-(1-(2-(4-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 607 [M + H]5-bromo-3-(1-(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 593 [M + H]5-bromo-3-(1-(2-[4-(5-bromo-4-ethylimidazol-1-yl)methyl]-1-methylpyrazol-3-yl]-5-fluorophenyl)ethoxy]-2-nitropyridine

m/z (ESI): 607 [M + H]5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(2-(1-(5-bromo-2-nitropyridin-3-yloxy)ethyl)-4-fluorophenyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 618 [M + H]5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazole-3-carbonitrile

m/z (ESI): 618 [M + H]5-bromo-3-(1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 661 [M + H]5-bromo-3-((2-(5-((4-bromo-3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 607 [M + H]5-bromo-3-(1-(2-(4-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)pyridin-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 604 [M + H]5-bromo-3-(1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 593 [M + H]5-bromo-3-((2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 579 [M + H]5-bromo-3-(1-(2-(3-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)pyridin-4-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 604 [M + H]5-bromo-3-(1-(2-(1-((5-bromo-1-cyclobutyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 619 [M + H]5-bromo-3-(1-(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-4-methyl-1H-imidazol-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 607 [M + H]5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-4-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyrimidine

m/z (ESI): 605 [M + H]5-bromo-3-{1-[2-(1-{[5-bromo-1-(2-fluoroethyl)-1H-pyrazol-4-yl]methyl}-1H-imidazol-2-yl)-5-fluorophenyl]ethoxy}-2-nitropyridine

m/z (ESI): 611 [M + H]5-bromo-3-(2-(4-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorobenzyloxy)-2-nitropyridine

m/z (ESI): 593 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-4-fluoro-1H-pyrazol-5-yl)methanone

m/z (ESI): 625 [M + H](R)-5-bromo-3-(1-(2-(3-(difluoromethyl)-5-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 565 [M + H]5-bromo-3-[(1R)-1-(2-{5-[(1-ethyl-1H-1,2,3-triazol-4-yl)methyl]-2-methyl-1,3-thiazol-4-yl}-5-fluorophenyl)ethoxy]-2-nitropyridine

m/z (ESI): 547 [M + H](R)-5-bromo-3-(1-(2-(4-((1-ethyl-3-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 543 [M + H]5-bromo-3-[(1R)-1-(2-{4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,5-dimethyl-1H-pyrazol-3-yl}-5-fluorophenyl)ethoxy]-2-nitropyridine

m/z (ESI): 543 [M + H](R)-5-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 537 [M + H]5-bromo-3-[(1R)-1-(2-{4-[(5-ethyl-1,2-thiazol-3-yl)methyl]-1-methyl-1H-pyrazol-3-yl}-5-fluorophenyl)ethoxy]-2-nitropyridine

m/z (ESI): 546 [M + H](R)-5-bromo-3-(1-(2-(5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 609 [M + H]5-bromo-3-[(1R)-1-(2-{5-[(1-ethyl-1H-1,2,3-triazol-4-yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-5-fluorophenyl)ethoxy]-2-nitropyridine

m/z (ESI): 584 [M + H](R)-5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-4-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl)isothiazole

m/z (ESI): 533 [M + H](R)-5-((1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 560 [M + H](R)-1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole

m/z (ESI): 395 [M + H](R)-5-((1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 594 [M + H]2-{2-[(1R)-1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl]-4-fluorophenyl}-3-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-5-fluoropyridine

m/z (ESI): 571 [M + H](R)-5-bromo-3-(1-(2-(3-chloro-5-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 576 [M + H](R)-3-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 540 [M + H](R)-3-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 537 [M + H]5-bromo-3-[(1R)-1-[2-(5-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-2-methyl-1,3-thiazol-4-yl)-5-fluorophenyl]ethoxy]-2-nitropyridine

m/z (ESI): 573 [M + H](R)-5-bromo-3-(1-(2-(3-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methyl)pyridin-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 553 [M + H](R)-5-((2′-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4′-fluoro-[1,1′-biphenyl]-2-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 536 [M + H](R)-5-((1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 576 [M + H](R)-4-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile

m/z (ESI): 577 [M + H](R)-5-bromo-3-(1-(2-(5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-methoxy-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 585 [M + H](R)-5-bromo-3-(1-(2-(5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 605 [M + H](R)-4-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-2-methylthiazole

m/z (ESI): 586 [M + H](R)-5-bromo-3-(1-(2-(5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 591 [M + H](R)-5-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-3-ethylisothiazole

m/z (ESI): 546 [M + H](R)-5-bromo-3-(1-(5-fluoro-2-(1-methyl-4-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)methyl)-1H-pyrazol-3-yl)phenyl)ethoxy)-2-nitropyridine

m/z (ESI): 557 [M + H](R)-5-bromo-3-(1-(2-(3-(difluoromethyl)-5-((1-ethyl-3-methoxy-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 595 [M + H](R)-5-bromo-3-(1-(2-(5-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methyl)-3-methoxy-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 572 [M + H](R)-5-bromo-3-(1-(2-(3-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)pyridin-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 552 [M + H](R)-5-bromo-3-(1-(2-(4-((3-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 607 [M + H](R)-5-bromo-3-(1-(2-(4-((1-ethyl-1H-pyrazol-4-yl)methyl)-5-methoxy-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 559 [M + H](R)-5-bromo-3-(1-(2-(1-(tert-butyl)-4-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 571 [M + H](R)-5-bromo-3-(1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)methyl)-5-methoxypyridin-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 556 [M + H](R)-5-bromo-3-(1-(2-(4-((1-ethyl-3-isopropyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 571 [M + H](R)-3-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-5-ethylisoxazole

m/z (ESI): 530 [M + H](R)-5-bromo-3-(1-(5-fluoro-2-(4-((1-isobutyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)phenyl)ethoxy)-2-nitropyridine

m/z (ESI): 557 [M + H](R)-4-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 554 [M + H]1-{[1-(2-{1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl}-4-fluorophenyl)-1H-pyrazol-5-yl]methyl}-1H-imidazole-4-carbonitrile

m/z (ESI): 512 [M + H]1-{[1-(2-{1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl}-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]methyl}-1H-imidazole-4-carbonitrile

m/z (ESI): 526 [M + H]1-((1-(2-(1-(5-bromo-2-nitropyridin-3-yloxy)ethyl)-4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 512 [M + H]1-((2-(2-(1-(5-bromo-2-nitropyridin-3-yloxy)ethyl)-4-fluorophenyl)-5-fluoropyridin-3-yl)methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 541 [M + H]1-{[4-(2-{1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl}-4-fluorophenyl)-2-methyl-1,3-thiazol-5-yl]methyl}-1H-imidazole-4-carbonitrile

m/z (ESI): 543 [M + H](1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone

m/z (ESI): 547 [M + H](R)-3-((1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

m/z (ESI): 642 [M + H]5-bromo-3-{1-[2-(5-{[1-(difluoromethyl)-1H-pyrazol-4-yl]methyl}-2-methyl-1,3-thiazol-4-yl)-5-fluorophenyl]ethoxy}-2-nitropyridine

m/z (ESI): 568 [M + H]5-bromo-3-(1-(2-(5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 619 [M + H]5-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-3-ethylisoxazole

m/z (ESI): 548 [M + H]5-((2-(2-(((5-bromo-2-nitropyridin-3-yl)oxy)methyl)-4-fluorophenyl)pyridin-3-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 523 [M + H]5-bromo-3-[1-(2-{4-[(1-ethyl-1H-1,2,3-triazol-4-yl)methyl]-1,2-thiazol-3-yl}-5-fluorophenyl)ethoxy]-2-nitropyridine

m/z (ESI): 533 [M + H]5-((1-(2-(((5-bromo-2-nitropyridin-3-yl)oxy)methyl)-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 546 [M + H]5-bromo-3-(1-(2-(5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 555 [M + H]5-{[4-(2-{[(5-bromo-2-nitropyridin-3-yl)oxy]methyl}-4-fluorophenyl)-2-methyl-1,3-thiazol-5-yl]methyl}-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 543 [M + H]4-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-5-((1-ethyl-1H-pyrazol-4-yl)methyl)-2-methyloxazole

m/z (ESI): 530 [M + H]5-bromo-3-((2-(5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 577 [M + H]5-bromo-3-((2-(5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 541 [M + H]5-bromo-3-((2-(5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 591 [M + H]5-bromo-3-(1-(2-(5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 569 [M + H]5-bromo-3-(1-(2-(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluoropyridin-3-yl)ethoxy)-2-nitropyridine

m/z (ESI): 564 [M + H]5-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)isothiazol-4-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 543 [M + H]5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-4-((1-ethyl-1H-pyrazol-4-yl)methyl)-3-methylisoxazole

m/z (ESI): 530 [M + H]3-((4-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 537 [M + H]3-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

m/z (ESI): 656 [M + H]1-((5-(4-fluoro-2-(1-(2-nitropyridin-3-yloxy)ethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 448 [M + H]3-(1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 540 [M + H]5-bromo-3-((2-(3-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 526 [M + H]4-(2-(((5-bromo-2-nitropyridin-3-yl)oxy)methyl)-4-fluorophenyl)-5-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)-2-methylthiazole

m/z (ESI): 546 [M + H]5-bromo-3-((2-(4-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 529 [M + H](R)-5-bromo-3-(1-(2-(5-((5-cyclobutyl-1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 555 [M + H](R)-5-bromo-3-(1-(2-(5-((5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 555 [M + H](R)-5-bromo-3-(1-(2-(4-((5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-3-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 569 [M + H](R)-5-bromo-3-(1-(2-(5-((3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)methyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 615 [M + H]

Synthesis of4-((2-chloropyridin-3-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile

To a solution of4-((2-chloropyridin-3-yl)(hydroxy)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile(450 mg, 1.56 mmol) in DCM (15 mL) was added SOCl₂ (0.34 mL, 4.7 mmol)at 0° C. under N₂. After stirring at r.t. for 2 h, the reaction wasconcentrated to afford crude4-(chloro(2-chloropyridin-3-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile(478 mg, 99% yield) as a colorless oil.

To a stirred solution of4-(chloro(2-chloropyridin-3-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile(478 mg, 1.56 mmol) in AcOH (12 mL) was added Zn powder (1.08 g, 15.6mmol). The reaction mixture was stirred at r.t. for 2 h under N₂ andthen concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (30% EtOAc in PE) to afford4-((2-chloropyridin-3-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile(160 mg, 38% yield) as a white solid. LC/MS(ESI)(m/z): 273 [M+H]⁺.

Synthesis of(5-(4-fluoro-2-formylphenyl)-1-methyl-1H-pyrazol-4-yl)methylmethanesulfonate

To a solution of5-fluoro-2-[4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl]benzaldehyde (50mg, 0.20 mmol) in DCM (5 mL) was added TEA (65 mg, 0.64 mmol), followedby the addition of MsCl (37 mg, 0.32 mmol) at 0° C. After stirring atr.t. for 1 h, the reaction was quenched with water and extracted withDCM twice, the combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography (silica gel, EtOAc/PE=2/1) to afford(5-(4-fluoro-2-formylphenyl)-1-methyl-1H-pyrazol-4-yl)methylmethanesulfonate (25 mg, 38% yield) as a yellow solid. LC/MS ESI (m/z):313 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(3-cyano-1-methyl-1H-pyrazol-5-yl)(3-(difluoromethyl)-1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)methyl methanesulfonate

m/z (ESI): 590 [M+ H](4-chloropyridin-3-yl)(5-cyano-1-methyl-1H-pyrazol-3-yl)methylmethanesulfonate

m/z (ESI): 327 [M + H]

Synthesis of5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole-3-carboxamide

To a stirred solution of ethyl5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole-3-carboxylate(1.10 g, 3.50 mmol) in MeOH (2 mL) was added a solution of NH₃ in MeOH(8 mL, 7 N) dropwise via syringe at r.t. After stirring at r.t. for 3 hin a sealed tube, the reaction was evaporated to give crude5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole-3-carboxamide (920mg, 92% yield) as a white solid. LC/MS (ESI) (m/z): 285 [M+H]⁺.

Synthesis of3-bromo-4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-(difluoromethyl)-1H-pyrazole

A solution of(3-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methanol(340 mg, 0.979 mmol) in TFA (2.0 mL) and TES (1.0 mL) was stirred atr.t. for 1 h. The reaction was concentrated. The residue was dilutedwith EtOAc (15 mL), washed with sat. NaHCO₃ (20 mL) and brine (15 mL),dried over anhydrous Na₂SO₄ and concentrated to dryness. The residue waspurified by column chromatography on silica gel (PE:EtOAc=3:1) to give3-bromo-4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-(difluoromethyl)-1H-pyrazole(300 mg, yield: 93%) as a yellow oil. LC/MS (ESI) m/z: 331 [M+H]⁺.

Synthesis of2-(2-bromo-4-fluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole

To a solution of 2-(2-bromo-4-fluorophenyl)-1H-imidazole (65.0 g, 270mmol) in DMF (300 mL) was added NaH (12.94 g, 323.6 mmol, 60% in mineraloil) portion-wise at 0° C. over 0.5 h. After the addition, the mixturewas stirred at 0° C. for another 30 min and then warmed to r.t. withstirring over 1 h. After cooling to 0° C.,[2-(chloromethoxy)ethyl]trimethylsilane (50.21 mL, 283.1 mmol) was addeddropwise, and the resulting mixture was stirred at r.t. for 3 h. Thereaction mixture was quenched with sat. aq. NH₄Cl (200 mL) at 0° C. andthen extracted with EA (2×300 mL). The combined organic extracts werewashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified by flash column chromatography onsilica-gel (30% EtOAc in PE) to afford2-(2-bromo-4-fluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(64 g, 64% yield) as a yellow solid. LC/MS ESI (m/z): 371 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

3-(1-(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)-2-(tert-butyldimethylsilyloxy)ethoxy)-2-nitropyridine

m/z (ESI): 645 [M + H]

Synthesis of 3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridin-2-amine

A mixture of (R)-3-(1-(5-fluoro-2-iodophenyl)ethoxy)-2-nitropyridine(15.5 g, 40.0 mmol), iron powder (22.4 g, 400 mmol) and NH₄Cl (21.6 g,400 mmol) in co-solvent of EtOH (550 mL) and H₂O (110 mL) was stirred at80° C. for 1 h. After cooling to r.t., the mixture was filtered, thefiltrate was concentrated under reduced pressure. The residue wasdiluted with DCM (500 mL), then washed with water and brine, dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography on silica gel (50% EtOAc in PE) to give3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridin-2-amine as a white solid(10.5 g, yield: 73%). LC/MS ESI (m/z): 359 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

3-(1-(5-fluoro-2-iodophenyl)ethoxy)pyridin-2-amine

m/z (ESI): 359 [M + H]3-[1-(2-{1-1(5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl]-1H-imidazol-2-yl}-5-fluorophenyl)-2-[(tert-butyldimethylsilyl)oxy]ethoxy]pyridin-2-amine

m/z (ESI): 615 [M + H]

Synthesis of3-((4-chloropyridin-3-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

A mixture of3-((4-chloropyridin-3-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile(500 mg, 2.01 mmol) and Pd/C (50 mg, 40%) in MeOH (8 mL) was stirred at25° C. under atmosphere of H₂ for 30 min. Then, die mixture was filteredthrough celite. The filtrate was concentrated in vacuo and the residuewas purified by column chromatography on silica gel (PE:EA=1:2, V/V) togive the target product as a yellow oil (100 mg, yield: 21%). LC/MS ESI(m/z): 233 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-ethyl-4-[(1-{4-fluoro-2-[(1R)-1-[(4-methoxyphenyl)methoxy]ethyl]phenyl}-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl]-1H-1,2,3-triazole

m/z (ESI): 504 [M + H](R)-5-((3-(difluoromethyl)-1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 496 [M + H]5-((3-chloro-1-(4-fluoro-2-(((4-methoxybenzyl)oxy)methyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 466 [M + H]

Synthesis of5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole-3-carbonitrile

A solution of5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole-3-carboxamide (920mg, 3.23 mmol) in POCl₃ (10 mL) was stirred at 110° C. for 3 h, thenconcentrated. The residue was partitioned between EtOAc (15 mL) and sat.NaHCO₃ (30 mL), the organic layer was washed with brine (30 mL), dried(MgSO₄) and evaporated. The residue was purified by columnchromatography on silica gel eluted (PE:EA=1:1) to give5-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)isoxazole-3-carbonitrile(750 mg, 87% yield) as a colorless oil. LC/MS (ESI) (m/z): 267 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-bromo-4-ethyl-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carbonitrile

m/z (ESI): 420 [M + H]

Synthesis of4-(2-bromo-4-fluorophenyl)-5-((1-ethyl-1H-pyrazol-4-yl)methyl)-2-methyloxazole

To a solution of1-(2-bromo-4-fluorophenyl)-3-(1-ethyl-1H-pyrazol-4-yl)propan-1-one (1.00g, 3.09 mmol) in CH₃C1 (20 mL) was added hydrobromic acid (0.4 mL, 33%in acetic acid) dropwise at 0° C. followed by the addition of Br₂ (494mg, 3.09 mmol) at 0° C. The reaction was stirred at 25° C. for 1.5 h.The reaction mixture was quenched with sat. aq. NH₄Cl and thenpartitioned between EtOAc and water. The organic layer was separated,washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography(PE/EA=3/1) to give2-bromo-1-(2-bromo-4-fluorophenyl)-3-(1-ethyl-1H-pyrazol-4-yl)propan-1-one(1.1 g, yield: 88%) as a yellow oil. LC/MS (ES+): m/z=403 [M+H]⁺.

To a solution of2-bromo-1-(2-bromo-4-fluorophenyl)-3-(1-ethyl-1H-pyrazol-4-yl)propan-1-one(1.10 g, 2.72 mmol) in MeOH (20 mL) was added sodium acetate (450 mg,5.44 mmol) at 25° C., and the mixture was stirred at 70° C. for 3 h. Thereaction was quenched by adding water (5 mL). The mixture was thenextracted with EA (3×10 mL), washed with sat. NH₄Cl (5 mL) and brine (5mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo to give crude1-(2-bromo-4-fluorophenyl)-3-(1-ethyl-1H-pyrazol-4-yl)-1-oxopropan-2-ylacetate (1.0 g, purity: ca. 50%) as a yellow gum.

To a solution of crude1-(2-bromo-4-fluorophenyl)-3-(1-ethyl-1H-pyrazol-4-yl)-1-oxopropan-2-ylacetate (1.0 g, 1.3 mmol, purity: ca. 50%) in acetic acid (5.0 mL) wasadded ammonium acetate (840 mg, 10.9 mmol) at 25° C., and the mixturewas stirred at 120° C. for 3 h. The reaction was quenched by addingwater (5 mL). The mixture was then extracted with EA (3×10 mL), washedwith sat. NH₄Cl (5 mL) and brine (5 mL), dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (EA in PE=0→50%) to give4-(2-bromo-4-fluorophenyl)-5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-methyl-1,3-oxazole(380 mg, yield: 38%) as a yellow gum. LC/MS (ES+): m/z=364 [M+H]⁺.

Synthesis of1-{[1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl]methyl}-1H-imidazole-4-carbonitrile

To a solution of[1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl]methanol (600 mg,1.81 mmol) in DCM (20 mL) was added SOCl₂ (0.260 mL, 3.61 mmol), andthen the mixture was stirred at 0° C. for 1 h. The mixture wasconcentrated to dryness. To the residue were added DMF (10 mL), K₂CO₃(749 mg, 5.42 mmol) and 1H-imidazole-4-carbonitrile (336 mg, 3.61 mmol).The resulting mixture was stirred at r.t. for 16 h. The reaction mixturewas quenched by ice water and then diluted with EtOAc. The organic layerwas separated, washed with sat. aq. NH₄Cl solution and brine, dried overanhydrous Na₂SO₄, filtered and concentrated to dryness. The residue waspurified by flash chromatography (silica gel, 0→50% EtOAc in PE) to give1-{[1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl]methyl}-1H-imidazole-4-carbonitrile(720 mg, 98%) as a yellow solid. LC/MS (ESI) m/z: 408 [M+H]⁺.

Synthesis of5-bromo-3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridin-2-amine

To a solution of 3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridin-2-amine(21.0 g, 58.6 mmol) in HOAc (2000 mL) at 0° C. was added the solution ofN-bromosuccinimide (12.52 g, 70.36 mmol) in HOAc (360 mL) dropwise over30 min. After the addition, the mixture was stirred at r.t. for 16 h.The reaction mixture was directly concentrated in vacuo and the residuewas purified by flash chromatography (0→20% EtOAc in PE) to give5-bromo-3-[(I1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridin-2-amine (10.5g, 41% yield) as a white solid. LC/MS ESI (m/z): 437 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-bromo-3-(1-(5-fluoro-2-iodophenyl)ethoxy)pyridin-2-amine

m/z (ESI): 437 [M + H]1-(2-[4-[(5-bromo-4-ethylimidazol-1-yl)methyl]-1-methylpyrazol-3-yl]-5-fluorophenyl)ethanol

m/z (ESI): 407 [M + H]

Synthesis of5-bromo-4-ethyl-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carboxamide

To a stirred solution of isoamyl nitrite (1.13 g, 9.67 mmol) and CuBr₂(1.73 g, 7.74 mmol) in MeCN (28 mL) was added a solution of ethyl5-amino-4-ethyl-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carboxylate(2.60 g, 6.45 mmol) in ACN (2 mL) at 0° C. under N₂. After stirring atr.t. for 12 h, the reaction was separated between EtOAc (30 mL) andwater (30 mL), the organic phase was dried over Na₂SO₄, thenconcentrated. The residue was purified by column chromatography onsilica gel eluted with PE/EtOAc (5:1→3:1) to give ethyl5-bromo-4-ethyl-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carboxylate(2.10 g, yield: 70%) as a yellow oil. LC/MS (ESI) (m/z): 467 [M+H]⁺.

To a solution of ethyl5-bromo-4-ethyl-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carboxylate(2.10 g, 4.50 mmol) in MeOH (10 mL), THF (10 mL) and water (10 mL) wasadded lithium hydroxide monohydrate (566 mg, 13.5 mmol) and the mixturewas stirred at 40° C. for 2 h. The mixture was concentrated, dilutedwith water (20 mL), and washed with EtOAc (15 mL). The aq. layer wasacidified with 1N aq. HCl to pH 3, the resulting solid was filtered anddried under reduced pressure to give5-bromo-4-ethyl-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carboxylicacid (1.60 g, yield: 81%) as white solid. LC/MS (ESI) (m/z): 439 [M+H]⁺.

To a mixture of compound5-bromo-4-ethyl-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carboxylicacid (1.98 g, 4.50 mmol) and NH₄Cl (2.41 g, 45.0 mmol) in DMF (20 mL)was added TEA (1.37 g, 13.5 mmol) and HATU (2.05 g, 5.40 mmol) at 0° C.The mixture was stirred at r.t. for 12 h, diluted with EtOAc (30 mL) andwashed with water (30 mL) and brine (15 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give compound5-bromo-4-ethyl-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carboxamide(1.50 g, yield: 76%) as a yellow oil. LC/MS (EST) (m/z): 438 [M+H]⁺.

Synthesis of1-((5-(4-fluoro-2-formylphenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-4-carbonitrile

To a solution of(5-(4-fluoro-2-formylphenyl)-1-methyl-1H-pyrazol-4-yl)methylmethanesulfonate (50 mg, 0.16 mmol) in DMF (3 mL) were added1H-imidazole-4-carbonitrile (18 mg, 0.19 mmol) and Cs₂CO₃ (104 mg, 0.320mmol). After stirring at 80° C. for 2 h, the reaction was quenched withwater and extracted twice with EtOAc. The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography (silica gel, EtOAc/PE=1/1) to afford1-((5-(4-fluoro-2-formylphenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-4-carbonitrile(12 mg, 24% yield) as a white solid. LC/MS ESI (m/z): 310 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorobenzaldehyde

m/z (ESI): 377 [M + H]2-(1-((5-bromo-1-cyclobutyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorobenzaldehyde

m/z (ESI): 403 [M + H]

Synthesis of(R)-1-(2-(5-((1-ethyl-1H-pyrazol-4-yl)methyl)oxazol-4-yl)-5-fluorophenyl)ethan-1-ol

A mixture of 4-bromo-5-((1-ethyl-1H-pyrazol-4-yl)methyl)oxazole (530 mg,2.07 mmol), (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol (412 mg,2.48 mmol), Pd(dppf)Cl₂ (151 mg, 0.21 mmol), and Na₂CO₃ (877 mg, 8.28mmol) in 1,4-dioxane (25 mL) and water (8 mL) was degassed three timeswith N₂, then stirred at 100° C. overnight. After overnight, thereaction mixture was cooled to r.t., filtered, and concentrated invacuo. The residue was purified by flash chromatography (0-500 EA in PE)to give(R)-1-(2-(5-((1-ethyl-H-pyrazol-4-yl)methyl)oxazol-4-yl)-5-fluorophenyl)ethan-1-ol(247 mg, 38% yield) as a red-brown gum. LC/MS ESI (m/z): 316 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-(2-(4-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 407 [M + H](R)-1-(2-(4-((3-(benzyloxy)-5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 513 [M + H](1R)-1-[2-(4-{[5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl]methyl}-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl]ethan-1-ol

m/z (ESI): 447 [M + H](1R)-1-[2-(1-{[5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl]methyl}-4-methyl-1H-imidazol-2-yl)-5-fluorophenyl]ethan-1-ol

m/z (ESI): 447 [M + H](R)-1-(2-(4-((5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-5-chloro-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 481 [M + H]1-(2-[4-[(4-ethylimidazol-1-yl)methyl]-1-methylpyrazol-3-yl]-5-fluorophenyl)ethanol

m/z (ESI): 329 [M + H]1-(2-(4-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)pyridin-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 404 [M + H]1-(2-(3-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)pyridin-4-yl)-5-fluorophenyl)ethanol

m/z (ESI): 404 [M + H]1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)pyrimidin-4-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 405 [M + H]1-(2-(3-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl)-5-fluoropyridin-2-yl)-5-fluorophenyl)ethanol

m/z (ESI): 345 [M + H](R)-1-(2-(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 363 [M + H](1R)-1-(2-{5-[(1-ethyl-1H-1,2,3-triazol-4-yl)methyl]-2-methyl-1,3-thiazol-4-yl}-5-fluorophenyl)ethan-1-ol

m/z (ESI): 347 [M + H](R)-1-(2-(4-((1-ethyl-3-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 343 [M + H](R)-5-((4-(4-fluoro-2-(1-hydroxyethyl)phenyl)-2-methylthiazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 357 [M + H](R)-1-(2-(4-((3-chloro-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 399 [M + H](1R)-1-[2-(4-{[1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl]methyl}-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl]ethan-1-ol

m/z (ESI): 379 [M + H](1R)-1-{2-[1-(difluoromethyl)-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1H-pyrazol-3-yl]-5-fluorophenyl}ethan-1-ol

m/z (ESI): 365 [M + H](1R)-1-(2-{4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,5-dimethyl-1H-pyrazol-3-yl}-5-fluorophenyl)ethan-1-ol

m/z (ESI): 343 [M + H]5-({2-[4-fluoro-2-(1-hydroxyethyl)phenyl]pyridine-3-yl}methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 337 [M + H](1R)-1-(2-{4-[(5-ethyl-1,2-thiazol-3-yl)methyl]-1-methyl-1H-pyrazol-3-yl}-5-fluorophenyl)ethan-1-ol

m/z (ESI): 346 [M + H](R)-1-(2-(4-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl)isothiazol-5-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 333 [M + H](R)-1-(2-(4-((1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 397 [M + H](R)-5-((4-(4-fluoro-2-(1-hydroxyethyl)phenyl)thiazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 343 [M + H](R)-1-(2-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 355 [M + H](R)-5-((5-fluoro-2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 355 [M + H](1R)-1-[2-(3-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-5-fluoropyridin-2-yl)-5-fluorophenyl]ethan-1-ol

m/z (ESI): 371 [M + H](R)-3-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 340 [M + H](R)-3-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 337 [M + H](1R)-1-[2-(5-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-2-methyl-1,3-thiazol-4-yl)-5-fluorophenyl]ethan-1-ol

m/z (ESI): 373 [M + H](R)-1-(2-(3-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methyl)pyridin-2-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 353 [M + H](R)-5-((4′-fluoro-2′-(1-hydroxyethyl)-1,1′-biphenyl]-2-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 336 [M + H](R)-1-(cyclopropylmethyl)-4-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-1H-pyrazole-3-carbonitrile

m/z (ESI): 377 [M + H](R)-1-(2-(5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-2-methylthiazol-4-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 386 [M + H](1R)-1-[2-(4-{[3-chloro-1-(cyclopropylmethyl)-1H-pyrazol-4-yl]methyl}-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl]ethan-1-ol

m/z (ESI): 389 [M + H](R)-1-(2-(4-((3-ethylisothiazol-5-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 346 [M + H](R)-1-(5-fluoro-2-(1-methyl-4-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)methyl)-1H-pyrazol-3-yl)phenyl)ethan-1-ol

m/z (ESI): 357 [M + H](R)-1-(2-(3-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)pyridin-2-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 366 [M + H](1R)-1-[2-(4-{[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]methyl}-1-ethyl-1H-pyrazol-3-yl)-5-fluorophenyl]ethan-1-ol

m/z (ESI): 369 [M + H](R)-1-(2-(3-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)pyridin-2-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 352 [M + H](R)-1-(2-(4-((3-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 407 [M + H](R)-1-(2-(4-((1-ethyl-1H-pyrazol-4-yl)methyl)-5-methoxy-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 359 [M + H](R)-1-(2-(1-(tert-butyl)-4-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 371 [M + H](1R)-1-(2-{3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-methoxypyridin-2-yl}-5-fluorophenyl)ethan-1-ol

m/z (ESI): 356 [M + H](R)-1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)methyl)-4-methoxypyridin-2-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 356 [M + H](R)-1-(2-(3-((4-(cyclopropylmethyl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 352 [M + H](1R)-1-[2-(4-{[1-ethyl-3-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl]ethan-1-ol

m/z (ESI): 371 [M + H](R)-1-(2-(4-((1,3-diethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 357 [M + H](R)-1-(2-(4-((5-ethylisoxazol-3-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 330 [M + H](R)-1-(2-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-(difluoromethyl)-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 391 [M + H](R)-1-(5-fluoro-2-(4-((1-isobutyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)phenyl)ethan-1-ol

m/z (ESI): 357 [M + H](1R)-1-{5-fluoro-2-[1-methyl-4-({1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}methyl)-1H-pyrazol-3-yl]phenyl}ethan-1-ol

m/z (ESI): 369 [M + H](R)-1-ethyl-4-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carbonitrile

m/z (ESI): 354 [M + H]1-((5-fluoro-2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 341 [M + H]1-((4-(4-fluoro-2-(1-hydroxyethyl)phenyl)thiazol-5-yl)methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 329 [M + H]1-({4-[4-fluoro-2-(1-hydroxyethyl)phenyl]-2-methyl-1,3-thiazol-5-yl}methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 343 [M + H]1-((4-(4-fluoro-2-(1-hydroxyethyl)phenyl)-2-methylthiazol-5-yl)methyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 343 [M + H](R)-3-((1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

m/z (ESI): 442 [M + H]1-(2-(5-((4-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methylthiazol-4-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 368 [M + H]1-[2-(5-{[1-(difluoromethyl)-1H-pyrazol-4-yl]methyl}-2-methyl-1,3-thiazol-4-yl)-5-fluorophenyl]ethan-1-ol

m/z (ESI): 368 [M + H]1-(2-(4-((3-ethylisoxazol-5-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-3,5-difluorophenyl)ethan-1-ol

m/z (ESI): 348 [M + H]1-((5-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 326 [M + H]3-((5-(5-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

m/z (ESI): 456 [M + H](R)-1-(2-(4-((3-ethylisoxazol-5-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 330 [M + H]1-(2-(4-((5-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrazol-5-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 407 [M + H](R)-1-(2-(4-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 343 [M + H](R)-1-(2-(4-((3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 379 [M + H](R)-1-(2-(5-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)-2-methylthiazol-4-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 360 [M + H](R)-1-(2-(5-((5-cyclobutyl-1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 355 [M + H](R)-1-(2-(4-((3-(cyclopropylmethyl)-1-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 369 [M + H](R)-1-(2-(5-((5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 355 [M + H](R)-1-(2-(4-((5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-3-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 369 [M + H]

Synthesis of diethyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3,5-dicarboxylate

To a solution of diethyl 1H-pyrazole-3,5-dicarboxylate (10.0 g, 47.1mmol) in THF (150 mL), was added sodium hydride (60%, dispersion inmineral oil, 2.07 g, 51.8 mmol) in portions at 0° C., and the resultingmixture was stirred at 0° C. for 30 min. Then a solution of(2-(chloromethoxy)ethyl)trimethylsilane (9.2 mL, 52 mmol) in THF (150mL) was added dropwise and the reaction mixture was stirred at r.t. for2 h. After 2 h, the reaction mixture was quenched by adding sat. aq.NH₄Cl solution (100 mL), extracted with EA (3×100 mL), combined allorganic phases, washed with brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel with EA in PE (0→10%, V/V) to give diethyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3,5-dicarboxylate (10.0g, 62%) as a yellow solid. LC/MS ESI (m/z): 343 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

3-((5-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

m/z (ESI): 369 [M + H]

Synthesis of(2-{5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-methyl-1,3-thiazol-4-yl}-5-fluorophenyl)methanol

A mixture of4-bromo-5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-methyl-1,3-thiazole (210mg, 0.73 mmol), 5-fluoro-1,3-dihydro-2,1-benzoxaborol-1-ol (223 mg, 1.47mmol), Pd(PPh₃)₄ (85 mg, 0.073 mmol) and disodium carbonate (156 mg,1.47 mmol), in EtOH (5 mL), water (2.5 mL), and toluene (1 mL) wasstirred at 95° C. for 4 h under an N₂ atmosphere. The reaction wasfiltered, and the filtrate was diluted with EA (50 mL), washed withbrine (2×20 mL), dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by flash chromatography (0→30% EtOAc in PE) to give(2-{5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-methyl-1,3-thiazol-4-yl}-5-fluorophenyl)methanol(220 mg, 47%). LC/MS ESI (m/z): 332 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-((2-(4-fluoro-2-(hydroxymethyl)phenyl)pyridin-3-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 323 [M + H]5-({4-[4-fluoro-2(hydroxymethyl)phenyl]-2-methyl-1,3-thiazol-5-yl}methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 343 [M + H](2-(4-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)methanol

m/z (ESI): 355 [M + H](2-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5fluorophenyl)methanol

m/z (ESI): 341 [M + H](2-(3-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)-5-fluorophenyl)methanol

m/z (ESI): 326 [M + H](2-(5-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)-2-methylthiazol-4-yl)-5-fluorophenyl)methanol

m/z (ESI): 346 [M + H](2-(4-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)methanol

m/z (ESI): 329 [M + H]

Synthesis of(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)methanol

To a mixture of2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorobenzaldehyde(380 mg, 1.01 mmol) in CH₃OH (5 mL) was added NaBH₄ (76.2 mg, 2.01 mmol)at 0° C. The reaction was stirred at 25° C. overnight. The mixture wasconcentrated tinder reduced pressure. EtOH (9 mL) and H₂O (1 mL) wereadded to this residue and the mixture was refluxed for 1 h. The mixtureconcentrated under reduced pressure to give a residue, which waspurified by column chromatography on silica gel eluted with PE/EtOAc(100:1→1:1) to give(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)methanol(0.3 g, yield: 79%) as a yellow oil. LC/MS ESI (m/z): 379 [M+H]⁺.

Synthesis of1-(2-{4-[(3-ethyl-1,2-oxazol-5-yl)methyl]-4H-1,2,4-triazol-3-yl}-5-fluorophenyl)ethan-1-ol

To a solution of 5-(azidomethyl)-3-ethyl-1,2-oxazole (3.00 g, 19.7 mmol)in EtOH/H₂O (30 mL, 1:1) were added Zn powder (6.45 g, 98.6 mmol) andNH₄Cl (10.55 g, 197.2 mmol). The mixture was stirred at 80° C. for 1 h.The reaction mixture was cooled and filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified by flashcolumn eluting with EA in PE (0-50%) to give(3-ethyl-1,2-oxazol-5-yl)methanamine (1.8 g, 72%) as a pale-yellow oil.LC/MS (ESI): m/z=127 [M+H]⁺.

A solution of(E)-N′-(4-fluoro-2-iodobenzoyl)-N,N-dimethylformohydrazonamide (2.80 g,8.36 mmol) and (3-ethyl-1,2-oxazol-5-yl)methanamine (1.05 g, 8.36 mmol)in AcOH (30 mL) was stirred for 16 h at 80° C. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved in EA(50 mL). The organic layer was washed with aq. NaHCO₃, dried overNa₂SO₄, filtered, and concentrated. The residue was purified by flashcolumn eluting with EA in PE (0→50%) to give4-[(3-ethyl-1,2-oxazol-5-yl)methyl]-3-(4-fluoro-2-iodophenyl)-4H-1,2,4-triazole(360 mg, 11%) as a yellow solid. MS (ESI): m/z=399 [M+H]⁺.

To a solution of4-[(3-ethyl-1,2-oxazol-5-yl)methyl]-3-(4-fluoro-2-iodophenyl)-4H-1,2,4-triazole(360 mg, 0.90 mmol), tributyl(1-ethoxyethenyl)stannane (327 mg, 0.900mmol), and CuI (17 mg, 0.09 mmol) in toluene (30 mL) was added Pd(PPh₃)₄(105 mg, 0.09 mmol). The reaction mixture was stirred for 16 h at 90°C., cooled, and filtered. The filtrate was concentrated under reducedpressure. The residue was dissolved in THF (10 mL) and 1 N aq. HCl (5mL) was added. The mixture was stirred for 1 h at r.t., neutralized withNa₂CO₃ to pH 8, and thrice extracted with EA (20 mL). The extracts weredried over Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by flash chromatography with EA in PE (0→50%). Theconcentrate was dissolved in MeOH (10 mL) and NaBH₄ (61.1 mg, 1.81 mmol)was added. The mixture was stirred for 0.5 h, then quenched with sat.aq. NH₄Cl, and extracted with EA (50 mL). The organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The residue waspurified by flash column eluting with MeOH in DCM (0→3%) to give1-(2-{4-[(3-ethyl-1,2-oxazol-5-yl)methyl]-4H-1,2,4-triazol-3-yl}-5-fluorophenyl)ethan-1-ol(80 mg, 28%) as a colorless oil. MS (ESI) m/z=317 [M+H]⁺.

Synthesis of1-{[1-(2-acetyl-4-fluorophenyl)-1H-pyrazol-5-yl]methyl}-1H-imidazole-4-carbonitrile

To a solution of1-{[1-(4-fluoro-2-iodophenyl)-1H-pyrazol-5-yl]methyl}-1H-imidazole-4-carbonitrile(1.70 g, 4.32 mmol) in toluene (20 mL) was added Pd(PPh₃)₄ (500 mg,0.430 mmol), tributyl(1-ethoxyethenyl)stannane (3.12 g, 8.64 mmol), andcatalytic CuI. The mixture was thrice degassed under N₂ and then stirredat 120° C. for 16 h. The reaction mixture was quenched with an aq. KFsolution and extracted with EtOAc. The separated organic layer wasconcentrated to dryness. Aq. HCl (10 mL, 1N) and THF (10 mL) were added,and the mixture was stirred at r.t. for 1 h. The mixture was twiceextracted with EtOAc, and the combined organic layers were washed withbrine, dried with anhydrous Na₂SO₄ and concentrated. The residue waspurified by flash chromatography (04% MeOH in DCM) to give1-{[1-(2-acetyl-4-fluorophenyl)-1H-pyrazol-5-yl]methyl}-1H-imidazole-4-carbonitrile(1.21 g, yield: 90%) as yellow oil. LC/MS (ESI) m/z: 310 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazol-1-yl)-5-fluorophenyl)ethanone

m/z (ESI): 392 [M + H]1-(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-4-methyl-1H-imidazol-2-yl)-5-fluorophenyl)ethanone

m/z (ESI): 405 [M + H]1-{[1-(2-acetyl-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]methyl}-1H-imidazole-4-carbonitrile

m/z (ESI): 324 [M + H]1-{[1-(2-acetyl-4-fluorophenyl)-1H-pyrazol-5-yl]methyl}-1H-pyrazole-4-carbonitrile

m/z (ESI): 310 [M + H]1-(2-(5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-one

m/z (ESI): 353 [M + H]1-(2-(5-((1-ethyl-1H-pyrazol-4-yl)methyl)-2-methyloxazol-4-yl)-5-fluorophenyl)ethan-1-one

m/z (ESI): 328 [M + H]1-(2-(4-((1-ethyl-1H-pyrazol-4-yl)methyl)-3-methylisoxazol-5-yl)-5-fluorophenyl)ethan-1-one

m/z (ESI): 328 [M + H]

Synthesis of3-bromo-2-(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluoropyridine

A mixture of(3-chloro-1-ethyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanol(500 mg, 1.36 mmol), 3-bromo-5-fluoro-2-(trimethylstannyl)pyridine (555mg, 1.63 mmol) and Pd(PPh₃)₄ (158 mg, 0.136 mmol) in toluene (20 mL) washeated to 110° C. under N₂ for 16 h. Toluene was removed by reducedpressure and this mixture was diluted by EtOAc (100 mL). This organicsolution was washed by brine (30 mL), dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (PE:EtOAc=1:1) to give3-bromo-2-(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluoropyridine(230 mg, yield: 28.7%) as colorless oil. LC/MS (ESI) (m/z): 398 [M+H]⁺.

Synthesis of(R)-5-bromo-3-(1-(5-fluoro-2-(trimethylstannyl)phenyl)ethoxy)pyridin-2-amine

To a solution of5-bromo-3-[(1R)-1-(5-fluoro-2-iodophenyl)ethoxy]pyridin-2-amine (4.60 g,10.5 mmol) in toluene (200 mL) was added tetrakis(triphenylphosphine)palladium (1.36 g, 1.18 mmol) and hexamethyldistannane (2.40 mL, 11.6mmol). The mixture was stirred at 110° C. for 12 h under an N₂atmosphere. After cooling to r.t., the mixture was treated with aq. KFand EtOAc and separated. The organic layer was washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography on silica gel (PE:EA=10:1, V/V) togive the target product (1.95 g, yield: 39%) as a white solid. LC/MS ESI(m/z): 475 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-bromo-3-(1-(5-fluoro-2-(trimethylstannyl)phenyl)ethoxy)pyridin-2-amine

m/z (ESI): 475 [M + H]

Synthesis of(5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(4-fluoro-2-iodophenyl)-1H-1,2,3-triazol-5-yl)methanone

A mixture of(E)-1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-3-(dimethylamino)prop-2-en-1-one(1.00 g, 3.67 mmol), 4-fluoro-2-iodoaniline (0.870 g, 3.67 mmol), I2(0.470 g, 1.83 mmol) and 4-methylbenzene-1-sulfonohydrazide (1.03 g,5.51 mmol) in DMSO (20 mL) was stirred at 110° C. under air for 12 h.After cooling to rt, the mixture was quenched with ice water andextracted with EA twice, the combined extracts were wash with brinetwice, dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue which was purified by silica gel column chromatography(DCM:MeOH=10:1, V/V) to give(5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(4-fluoro-2-iodophenyl)-1H-1,2,3-triazol-5-yl)methanoneas brown oil (700 mg, yield: 38%). LC/MS ESI (m/z): 490 [M+H]⁺.

Synthesis of(R)-1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-1H-pyrazole-3-carbaldehyde

To a solution of 1H-pyrazole-3-carbaldehyde (2.00 g, 20.8 mmol),(R)-2-(1-(benzyloxy)ethyl)-4-fluoro-1-iodobenzene (8.10 g, 22.9 mmol),N,N′-dimethylcyclohexane-1,2-diamine (592 mg, 4.20 mmol) and K₂CO₃ (5.70g, 41.6 mmol) in NMP (30 mL) was added CuI (396 mg, 2.10 mmol). Themixture was stirred at 150° C. for 16 h. The reaction was diluted withEtOAc and washed first with H₂O, and then with brine. The organic layerwas dried over anhydrous Na₂SO₄, filtered, and concentrated. The residuewas purified by flash chromatography (silica gel, 0→11% EA in PE) togive(R)-1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-1H-pyrazole-3-carbaldehyde(500 mg, 7% yield) as a yellow oil. LC/MS (ESI) m/z: 325 [M+H]⁺.

Synthesis of2-(5-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazol-3-yl)ethanol

To a solution of3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-5-[(oxan-2-yloxy)methyl]-1,2-oxazole(3.40 g, 9.96 mmol) in THF (30 mL) was added TBAF (1 M in THF, 9.96 mL,9.96 mmol) dropwise over 5 min at 0° C. The resulting solution wasstirred at 25° C. for 1 h. Then, the solution was diluted with EtOAc (50mL) and washed with sat. NH₄Cl (50 mL×2). The organic phase wasconcentrated in vacuo and the residue was purified by flashchromatography (0→20% MeOH in DCM) to give2-{5-[(oxan-2-yloxy)methyl]-1,2-oxazol-3-yl}ethan-1-ol (1.8 g, 80%yield) as a pale-yellow oil. LC/MS (ESI): m/z=228[M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(2-{3-chloro-5-[1-(cyclopropylmethyl)-1H-1,2,3-triazole-4-carbonyl]-1H-pyrazol-1-yl}-5-fluorophenyl)methanol

m/z (ESI): 376 [M + H]

Synthesis of1-[5-fluoro-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)phenyl]ethane-1,2-diol

To a solution of2-(2-ethynyl-4-fluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole(5.00 g, 15.5 mmol) and pyridine (1.24 g, 15.5 mmol) in acetone (50 mL)and H₂O (10 mL) were added NMO (7.28 g, 31.1 mmol) and K₂OsO₄.2H₂O (60mg, 0.16 mmol). The reaction mixture was heated to reflux and stirredfor 18 h. The mixture was evaporated under reduced pressure and theresidue was partitioned between EtOAc and water. The layers wereseparated, and the aq. layer was thrice extracted with EtOAc. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel eluted with PE:EA=1:1 togive1-[5-fluoro-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)phenyl]ethane-1,2-diol(3.50 g, 63%) as an oil. LC/MS ESI (m/z): 353 [M+H]⁺.

Synthesis of5-((3-(2-acetyl-4-fluorophenyl)isothiazol-4-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

To a solution of5-((3-(2-bromo-4-fluorophenyl)-1,2-thiazol-4-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(0.91 g, 2.4 mmol) in toluene (10 mL) were addedtributyl(1-ethoxyethenyl)stannane (1.47 g, 4.08 mmol) and Pd(PPh₃)₄(0.28 g, 0.24 mmol). The reaction mixture stirred at 100° C. for 18 hunder N₂. This mixture was concentrated and then diluted with THF (10mL) and HCl (2 mL, 1 N). The mixture was stirred at r.t. for 2 h. Thereaction mixture was diluted with ethyl acetate (20 mL) and washed withwater (3×20 mL). The organic layer was washed with brine (20 mL), driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (30% to 50of EA in PE) to give5-((3-(2-acetyl-4-fluorophenyl)isothiazol-4-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(779 mg, 95% yield) as a colorless oil. LC/MS (ESI) m/z: 341.0 [M+H]⁺.

Synthesis of(2-(4-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)methanol

To a mixture of5-bromo-1-ethyl-4-((4-iodo-1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazole(200 mg, 0.510 mmol) and(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)trimethylstannane (184 mg, 0.560mmol) in DMF (8 mL) was added LiCl (43 mg, 1.0 mmol), CuCl (100 mg, 1.01mmol) and Pd(PPh₃)₄ (59 mg, 0.051 mmol). The mixture was thrice degassedwith N₂ and stirred at 100° C. under a N₂ atmosphere for 8 h. Aftercooling to r.t., the mixture was poured into water (50 mL) and EtOAc (20mL). The aq. layer was twice extracted with EtOAc (10 mL). The combinedextracts were washed with brine (2×20 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography on silica gel (10→25% EtOAc in PE) to give3-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-4-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazoleas a white solid (170 mg, yield: 69%). LC/MS ESI (m/z): 435 [M+H]⁺.

To a solution of3-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-4-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazole(300 mg, 0.62 mmol) in THF (2 mL) was added conc. HCl (0.26 mL, 3.1mmol, 12 N) at 0° C. The mixture was stirred at r.t. for 3 h. Thereaction mixture was treated with sat. aq. Na₂CO₃ solution (10 mL) andextracted with EtOAc (2×10 mL). The combined extracts were washed withbrine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated.The residue was dissolved in MeOH (2 mL). To this solution was addedNaBH₄ (32 mg, 0.93 mmol) at 0° C., and the resulting mixture was stirredat r.t. for 3 h. The mixture was diluted with water (20 mL) andextracted with EtOAc (2×10 mL). The combined extracts were washed withbrine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated.The residue was purified by column chromatography on silica gel (eluent:25→50% EtOAc in PE) to give(2-(4-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)methanolas a colorless oil (190 mg, yield: 78%). LC/MS ESI (m/z): 393 [M+H]⁺.

Synthesis of1-((1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazole-4-carbonitrile

To a solution of1-((1-(2-acetyl-4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazole-4-carbonitrile(480 mg, 1.55 mmol) in MeOH (10 mL) was added NaBH₄ (117 mg, 3.11 mmol)at 0° C. under N₂ atmosphere. After the addition, the resulting solutionwas stirred at r.t. for 3 h. After cooling to 0° C., the reactionmixture was treated with DCM (20 mL) and water (20 mL), the organiclayer was separated, and the aq. layer was extracted with DCM (20 mL).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography (0→100% EtOAc in PE) to give1-((1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazole-4-carbonitrile(380 mg, yield: 79%) as a colorless oil. LC/MS ESI (m/z): 312 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(4-fluoro-2-iodophenyl)-1H-1,2,3-triazol-5-yl)methanol

m/z (ESI): 492 [M + H]1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 394 [M + H]5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazole-3-carbonitrile

m/z (ESI): 418 [M + H]1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 393 [M + H]1-(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-4-methyl-1H-imidazol-2-yl)-5-fluorophenyl)ethanol

m/z (ESI): 407 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazol-5-yl)methanol

m/z (ESI): 609 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-4-fluoro-1H-pyrazol-5-yl)methanol

m/z (ESI): 627 [M + H]1-(2-(5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 363 [M + H](1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 549 [M + H](1-(2-(((5-bromo-2-nitropyridin-3-yl)oxy)methyl)-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 551 [M + H][1-(2-{[(5-bromo-2-nitropyridin-3-yl)oxy]methyl}-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl][1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methanol

m/z (ESI): 578 [M + H]1-(2-{4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,2-oxazol-3-yl}-5-fluorophenyl)ethan-1-ol

m/z (ESI): 316 [M + H]1-(2-{4-[(1-ethyl-1H-1,2,3-triazol-4-yl)methyl]-1,2-thiazol-3-yl}-5-fluorophenyl)ethan-1-ol

m/z (ESI): 333 [M + H]5-((1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 340 [M + H]1-(2-(5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5fluorophenyl)ethan-1-ol

m/z (ESI): 355 [M + H]1-(2-(5-((1-ethyl-1H-pyrazol-4-yl)methyl)-2-methyloxazol-4-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 330 [M + H]1-(2-(5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 369 [M + H]1-(2-(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluoropyridin-3-yl)ethan-1-ol

m/z (ESI): 364 [M + H]5-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)isothiazol-4-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 343 [M + H]1-(2-{4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-methyl-1,2-oxazol-5-yl}-5-fluorophenyl)ethan-1-ol

m/z (ESI): 330 [M + H]3-((1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazol-5-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

m/z (EST): 542 [M + H]

Synthesis of1-(2-{4-[(1-ethyl-1H-1,2,3-triazol-4-yl)methyl]-1,2-thiazol-3-yl}-5-fluorophenyl)ethan-1-one

To a solution of1-ethyl-4-{[3-(4-fluoro-2-iodophenyl)-1,2-thiazol-4-yl]methyl}-1H-1,2,3-triazole(75 mg, 0.18 mmol) in toluene (3 mL) was addedtributyl(1-ethoxyethenyl)stannane (131 mg, 0.362 mmol), and Pd(PPh₃)₄(21 mg, 0.018 mmol). The mixture was stirred at 100° C. for 16 h andthen concentrated in vacuo. To the residue was added THF (5 mL) and aq.HCl (1 mL, 1 M). The mixture was stirred at r.t. for 2 h and then pouredinto water (80 mL) and extracted with EA (80 mL×3). The organic layerwas washed with sat. aq. NaCl (60 mL×2), dried over anhydrous Na₂SO₄,and filtered. The filtrate concentrated in vacuo, and the residue waspurified by column chromatography on silica gel eluted with PE:EA=3:1 toafford1-(2-{4-[(1-ethyl-1H-1,2,3-triazol-4-yl)methyl]-1,2-thiazol-3-yl}-5-fluorophenyl)ethan-1-one(30 mg, 50%) as a light-yellow solid. LC/MS (EST): m/z=331 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-(2-(3-bromo-5-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-one

m/z (ESI): 391 [M + H]5-((1-(2-acetyl-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 338 [M + H]1-(2-(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluoropyridin-3-yl)ethan-1-one

m/z (ESI): 362 [M + H]

Synthesis of(R)-8-fluoro-6-methyl-4H,6H-benzo[e]pyrazolo[5,1-c][1,4,2]oxazaborepin-4-ol

LDA (5.52 mL, 5.52 mmol, 1.0 N in THF) was added dropwise to a solutionof1-{4-fluoro-2-[(1R)-1-[(4-methoxyphenyl)methoxy]ethyl]phenyl}-1H-pyrazole(1.80 g, 5.52 mmol) in THF (80 mL) at −78° C. over 5 min. After theaddition, the mixture was stirred at −78° C. under N₂ for 1 h. Trimethylborate (0.480 g, 4.60 mmol) was added dropwise at −78° C. and thereaction mixture was warmed slowly to r.t. with stirring overnight underN₂. The mixture was poured into ice-water and twice extracted withEtOAc. The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated. The residue was dissolvedin DCM (100 mL), followed by the addition of TFA (10 mL). The resultingmixture was stirred at r.t. for 1 h. The mixture was concentrated andthe residue was purified by column chromatography (silica gel, 1→10%ethyl acetate in petroleum ether) to afford(9R)-12-fluoro-9-methyl-8-oxa-2,3-diaza-7-boratricyclo[8.4.0.0{circumflexover ( )}{2,6}]tetradeca-1(14),3,5,10,12-pentaen-7-ol (1.1 g, 86%) as awhite solid. LC/MS (ESI) m/z: 233 [M+H]⁺.

Synthesis of3-((4-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile

To a solution of3-((4-chloropyridin-3-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile(100 mg, 0.258 mmol) in DME (3 mL) was added5-fluoro-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol (107 mg, 0.644 mmol),X-Phos (43 mg, 0.086 mmol), Pd(dppf)Cl₂ (21 mg, 0.025 mmol), Cs₂CO₃ (420mg, 1.29 mmol) and H₂O (1 mL). After degassing with N₂ three times, themixture was stirred at 90° C. for 4 h. The mixture was allowed to coolto 25° C. and then diluted with DCM and water. The organic layer wasseparated, washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel (PE:EA=1:3, V/V) to give the target product as a white solid(60 mg, yield: 41%). LC/MS EST (m/z): 337 [M+H]⁺.

Synthesis of(3-chloro-1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone

To a solution of2-(3-chloro-5-(1-ethyl-1H-pyrazole-4-carbonyl)-1H-pyrazol-1-yl)-5-fluorobenzaldehyde(400 mg, 1.15 mmol) in anhydrous THF (20 mL) was addedbromo(methyl)magnesium (1.92 mL, 1.15 mmol, 0.6 M in THF) dropwise at−30° C. After the addition, the resulting mixture was stirred at −30° C.for 0.5 h. The reaction mixture was quenched with sat. aq. NH₄Clsolution (20 mL) and then extracted with EA (20 mL). The extract waswashed with brine (20 mL) and concentrated in vacuo to give the residue,which was purified by flash chromatography (0-100% EA in PE, V/V) togive(3-chloro-1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone(350 mg, 84%) as a white solid. LC/MS (ESI): m/z=363 [M+H]⁺.

Synthesis of1-(2-{4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,2-oxazol-3-yl}-5-fluorophenyl)ethan-1-one

To a solution of3-(2-bromo-4-fluorophenyl)-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,2-oxazole(313 mg, 0.894 mmol) in toluene (8 mL) was added Pd(PPh₃)₄ (103 mg,0.089 mmol), CuI (17 mg, 0.089 mmol) andtributyl(1-ethoxyethenyl)stannane (484 mg, 1.34 mmol) at r.t. Thereaction was thrice degassed under N₂ atmosphere and stirred at 100° C.for 16 h. The reaction mixture was concentrated, and the residue wasstirred in THF (8 mL) and conc. HCl (3.6 mL) for 1 h. sat. aq. KFsolution (20 mL) was added, and the reaction was stirred for another 1h. The resulting solid was filtered, the residue was diluted with EtOAc(10 mL), washed with sat. NaHCO₃ (10 mL) and brine (15 mL), dried overNa₂SO₄ and concentrated to dryness to give crude1-(2-{4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,2-oxazol-3-yl}-5-fluorophenyl)ethan-1-one(629 mg) as a brown oil. LC/MS (ESI) m/z: 314 [M+H]⁺.

Synthesis of3-((5-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile

A mixture of3-[(5-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carbaldehyde(1.30 g, 3.13 mmol), hydroxylamine hydrochloride (0.390 g, 5.63 mmol)and NaOAc (0.770 g, 5.63 mmol) in EtOH (40 mL) was stirred at 50° C. for2 h. After cooling to r.t., the mixture was concentrated under reducedpressure. The residue was diluted with DCM (40 mL), then washed withwater and brine, dried over anhydrous Na₂SO₄, filtered and concentratedto give crude3-((5-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbaldehydeoxime (1.33 g, yield: 94%). LC-MS (ESI): m/z 430 [M+H]⁺.

To a solution of3-((5-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbaldehydeoxime (1.2 g, 2.8 mmol) in THF (30 mL) at 0° C. was added SOCl₂ (1.26 g,10.6 mmol) dropwise. After the addition, the mixture was stirred at r.t.for 2 h. The mixture was concentrated under reduced pressure to givecrude3-((5-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile(1.2 g, yield: 99%). LC-MS (ESI): m/z 412 [M+H]⁺.

Synthesis of3-[(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrazole-5-carbonitrile

To a solution of3-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile(638 mg, 1.39 mmol) in DCM (15 mL) was added Et₃SiH (0.67 mL, 4.2 mmol)at 0° C. and TFA (0.41 mL, 5.6 mmol) and then the mixture was stirred at0° C. for 1 h. The reaction was concentrated. The residue was dilutedwith EtOAc (15 mL), washed with sat. NaHCO₃ (20 mL) and brine (15 mL),dried over anhydrous Na₂SO₄ and concentrated to dryness. The residue waspurified by flash column chromatography on silica gel (PE:EtOAc=3:1) togive3-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile(600 mg, yield: 97%) as a colorless oil. LC/MS (ESI) m/z: 444.1 [M+H]⁺.

To a solution of3-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile(276 mg, 0.623 mmol) in DCM (3 mL) was added TFA (3.0 mL, 40.4 mmol) andthen the mixture was stirred at 25° C. for 16 h. The mixture wasconcentrated, and the residue was diluted with CH₃CN (3 mL). Aq. ammonia(1 mL) was added to this solution at 0° C. and the mixture was stirredat 25° C. for 1 h. The reaction was concentrated, diluted with EtOAc (15mL). The organic solution was washed with brine (15 mL), dried overanhydrous Na₂SO₄ and then concentrated. The residue was purified byflash column chromatography (silica gel, 50→75% EtOAc in PE) to give3-[(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrazole-5-carbonitrile(103 mg, yield: 53% yield) as a white solid. LC/MS (ESI) m/z: 314.0[M+H]⁺.

Synthesis of1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-1-yl)-5-fluorophenyl)ethanone

To a solution of5-bromo-1-ethyl-4-((1-(4-fluoro-2-iodophenyl)-1H-imidazol-5-yl)methyl)-1H-pyrazole(500 mg, 1.05 mmol), tributyl(1-ethoxyethenyl)stannane (760 mg, 2.10mmol) and CuI (10 mg, 0.052 mmol) in toluene (50 mL) was added Pd(PPh₃)₄(243 mg, 0.210 mmol) under N₂. The resulting mixture was stirred at 100°C. under N₂ for 48 h. The mixture was cooled to r.t., then 1 N aq. HCl(20 mL) and THF (30 mL) were added. The resulted mixture was stirred atr.t. for another 2 h before neutralization with sat. Na₂CO₃ to pH 8. Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel (0→5% MeOH in DCM) to give1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-1-yl)-5-fluorophenyl)ethanone(80 mg, 19% yield) as a yellow solid. LC/MS (ESI): m/z=391 [M+H]⁺.

Synthesis of(4-bromo-3-ethyl-1-methyl-1H-pyrazol-5-yl)(1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methanol

To a stirred solution of(3-ethyl-1-methyl-1H-pyrazol-5-yl)(1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methanol(350 mg, 0.79 mmol) in N,N-dimethylformamide (8 mL) was added a solutionof 1-bromopyrrolidine-2,5-dione (142 mg, 0.79 mmol) inN,N-dimethylformamide (1 mL) at 0° C. The reaction was stirred at 0° C.for 1 h. The reaction mixture was poured into water (10 mL) andextracted with EtOAc (20 mL×3). The combined organic phases were washedwith brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated todryness. The residue was purified by flash column chromatography onsilica gel (PE:EtOAc=1:1, V/V) to give(4-bromo-3-ethyl-1-methyl-1H-pyrazol-5-yl)(1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methanol(0.40 g, 87% yield) as a yellow oil. LC/MS (ESI) (m/z): 519.0 [M+H]⁺.

Synthesis of3-(2,2-difluoroethyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazole

To a solution of crude2-{5-[(oxan-2-yloxy)methyl]-1,2-oxazol-3-yl}acetaldehyde (3.19 g, 7.50mmol) in dry DCM (60 mL) was added DAST (2.4 mL, 18 mmol) dropwise at 0°C. over 5 min. The resulting mixture was stirred at 0° C. for 2 h, thenthe solution was slowly poured into cold sat. aq. NaHCO₃ (100 mL) withvigorous stirring. After 10 min, the mixture was extracted twice withDCM. The combined extracts were washed with brine, concentrated andpurified by column chromatography on silica gel (0→40% EA in PE) to give3-(2,2-difluoroethyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazole(900 mg, 49% yield over 2 steps) as a colorless oil. LC/MS (ESI):m/z=248 [M+H]⁺.

Synthesis of(R)-3-((1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-isopropyl-1H-pyrazole-5-carbonitrile

To a solution of4-bromo-3-(bromomethyl)-1-isopropyl-1H-pyrazole-5-carbonitrile (100 mg,0.33 mmol) and(R)-8-fluoro-6-methyl-4H,6H-benzo[e]pyrazolo[5,1-c][1,4,2]oxazaborepin-4-ol(83 mg, 0.36 mmol) in toluene (10 mL) and EtOH (2 mL) were addedpotassium phosphate (207 mg, 0.98 mmol) and Pd(PPh₃)₄ (38 mg, 0.03 mmol)at r.t. The mixture was thrice degassed under N₂ atmosphere and stirredat 90° C. for 12 h. The reaction mixture was filtered, and the filtratewas concentrated to dryness. The residue was purified by prep-TLC(PE:EtOAc=3:1, V/V) to give(R)-3-((1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-isopropyl-1H-pyrazole-5-carbonitrile(20 mg, 14% yield) as a yellow oil. LC/MS (ESI) (m/z): 354 [M+H]⁺.

Synthesis of(R)-1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)methyl)-6-methoxypyridin-2-yl)-5-fluorophenyl)ethan-1-ol

To a solution of2-chloro-3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-methoxypyridine (140 mg,0.56 mmol) and (3R)-5-fluoro-3-methyl-1,3-dihydro-2,1-benzoxaborol-1-ol(92 mg, 0.56 mmol) in THF (5 mL) and H₂O (1 mL) was added K₃PO₄ (236 mg,1.11 mmol). The mixture was degassed with N₂ three times and then[1,1′-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (36 mg,0.056 mmol) was added. The mixture was degassed with N₂ once again andstirred at 70° C. overnight. After cooling to r.t. and concentration invacuo, the residue was purified by flash column chromatography (silicagel, 0-50% EA in PE) to give(1R)-1-(2-{3-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-methoxypyridin-2-yl}-5-fluorophenyl)ethan-1-ol(140 mg, yield: 71%) as a yellow foam. LC/MS ESI (m/z): 356 [M+H]⁺.

Synthesis of5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazole

To a solution of(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)(1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methanol(460 mg, 1.02 mmol) in CH₃CN (5 mL) was added iodotrimethylsilane (1.45mL, 10.2 mmol) at r.t. The mixture was stirred at 90° C. for 2 h. Afterconcentration to remove CH₃CN, the resulting residue was treated withEtOAc and aq. Na₂CO₃. The organic layer was separated, concentratedunder reduced pressure and purified by flash chromatography on silicagel (10→50% EA in PE) to give5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazole(300 mg, 67% yield) as a white solid. LC/MS (ESI): m/z=437 [M+H]⁺.

Synthesis of1-(2-(5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-one

A suspension of5-[(3-chloro-1-ethyl-1H-pyrazol-4-yl)methyl]-1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazole(19.5 g, 43.9 mmol) and Pd(OAc)₂ (247 mg, 1.10 mmol),1,3-bis(diphenylphosphino)propane (905 mg, 2.19 mmol) in1-butyl-3-methylimidazolium tetrafluoroborate (150 mL) was stirred for10 min. After the mixture was degassed three times, 1-(vinyloxy)butane(21.96 g, 219.6 mmol) and TEA (7.31 mL, 52.7 mmol) were addedsequentially. The mixture was stirred for 24 h at 115° C. The mixturecooled to r.t., and then TN aq. HCl was added. After stirring for 0.5 h,dichloromethane was added. The organic layer was washed with brine,dried over anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The crude residue was purified by flash columnchromatography on silica gel to give1-(2-{5-[(3-chloro-1-ethyl-1Hpyrazol-4-yl)methyl]-3-methyl-1H-pyrazol-1-yl}-5-fluorophenyl)ethan-1-one(11.1 g, yield: 70%) as a white foam. LC/MS (ESI): m/z=361 [M+H]⁺.

Synthesis of methyl2-(5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorobenzoate

A mixture of5-{[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]methyl}-1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazole(340 mg, 0.779 mmol), MeOH (10 mL), Pd(dppf)Cl₂ (57 mg, 0.078 mmol) andTEA (236 mg, 2.33 mmol) was stirred for 16 h under a CO balloon at 25°C. The reaction mixture was concentrated and diluted with DCM. Thissolution was washed with brine, dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified by flash columnchromatography (silica gel, 0→50% EA in PE) to give methyl2-(5-{[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]methyl}-3-methyl-1H-pyrazol-1-yl)-5-fluorobenzoate(280 mg, 98%) as a colorless oil. LC/MS (ESI) m/z: 369 [M+H]⁺.

Synthesis of(1-ethyl-1H-pyrazol-4-yl)(1-(4-fluoro-2-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol

To a solution of{5-fluoro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}methanol (260mg, 0.990 mmol) in dry THF (2 mL) was added n-BuLi (0.990 mL, 2.49 mmol,2.5 M) dropwise at −78° C. over 5 min. The solution was stirred at −70°C. for 1 h. To this solution was added1-ethyl-1H-pyrazole-4-carbaldehyde (186 mg, 1.49 mmol) in THF (2 mL)dropwise. The solution was warmed slowly to 0° C. while stirring over0.5 h. The mixture was poured into cold sat. NH₄Cl and then extractedwith EA twice. The combined extracts were washed with brine,concentrated under vacuum and purified by flash chromatography (0→100%EtOAc in PE) to give(1-ethyl-1H-pyrazol-4-yl)({1-[4-fluoro-2-(hydroxymethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl})methanol(270 mg, 70%) as a colorless syrup. LC/MS (ESI): m/z=385 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(1-{2-[(1R)-1-(benzyloxy)ethyl]-4-fluorophenyl}-3-(difluoromethyl)-1H-pyrazol-5-yl)[3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol-5-yl]methanol

m/z (ESI): 521 [M + H]

Synthesis of 3-(2,2-difluoroethyl)isoxazole-5-carbaldehyde

To a solution of [3-(2,2-difluoroethyl)-1,2-oxazol-5-yl]methanol (580mg, 3.56 mmol) in DCM (40 mL) was added Dess-Martin periodinane (1.58 g,3.73 mmol) in three portions at 0° C. The resulting mixture was stirredat 0° C. for 1 h. The mixture was diluted with DCM (100 mL), and washedwith sat. NaHCO₃ (50 mL×2) and brine (30 mL). The organic layer wasconcentrated in vacuo and the residue was purified by columnchromatography on silica gel (20% EtOAc in PE) to give3-(2,2-difluoroethyl)-1,2-oxazole-5-carbaldehyde (330 mg, 58 over 2steps) as a light-yellow oil. LC/MS (ESI): m/z=162 [M+H]⁺.

Synthesis of(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone

To a solution of(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol(2.18 g, 5.87 mmol) in dioxane (15 mL) was added MnO₂ (2.01 g, 29.3mmol) in one portion. The reaction mixture was then warmed to 100° C.and stirred at that temperature for 16 h. The reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give the crudeproduct, which was purified by column chromatography on silica gel(0→20% EtOAc in PE) to give(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone(1.84 g, 85% yield) as a yellow solid. TLC: R_(f)=0.3 (PE/EA=2:1), LC/MSESI (m/z): 371 [M+H]⁺.

Synthesis of(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-3-fluoro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone

To a solution of(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-3-fluoro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol(941 mg, 2.50 mmol) in DCM (30 mL) was added Dess-Martin periodinane(1.59 g, 3.75 mmol). Then the mixture was stirred at r.t. for 1 h. After1 h, the reaction mixture was filtered, the filtrate was concentrated invacuo to give the crude product. The crude product was purified byprep-TLC (MeOH/DCM=1/30, V/V) to give(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-3-fluoro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone(2.49 g, 87%) as a light yellow gum. LC/MS ESI (m/z): 375 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-pyrazol-5-yl)(5-bromo-1-ethyl-1H-pyrazol-4-yl)methanone

m/z (ESI): 435 [M + H](1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-4-fluoro-1H-pyrazol-5-yl)(5-bromo-1-ethyl-1H-pyrazol-4-yl)methanone

m/z (ESI): 453 [M + H]5-(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-pyrazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbaldehyde

m/z (ESI): 487 [M + H]

Synthesis of1-(2-(5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-one

To a solution of1-(cyclopropylmethyl)-4-((1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-3-methyl-1H-pyrazole(1.70 g, 3.80 mmol) in ionic liquid (10 mL) were added[3-(diphenylphosphanyl)propyl]diphenylphosphane (0.08 g, 0.19 mmol),triethylamine (0.60 mL, 4.5 mmol), Pd(OAc)₂ (30 mg, 0.11 mmol) and1-(ethenyloxy)butane (2.5 mL, 19 mmol) under N₂ atmosphere. The mixturewas thrice degassed tinder N₂ atmosphere and stirred at 115° C. tinderN₂ atmosphere for 24 h. The mixture was diluted with EtOAc (15 mL),washed with water (5 mL) and brine (5 mL), dried over anhydrous Na₂SO₄and concentrated to dryness. The residue was purified by flash columnchromatography on silica gel (PE:EtOAc=1:1, V/V) to give1-(2-(5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-one(300 mg, 22%) as a yellow oil. LC/MS (ESI) (m/z): 367 [M+H]⁺.

Synthesis of5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(2-(1-ethoxyvinyl)-4-fluorophenyl)-1H-pyrazole-4-carbonitrile

To a solution of5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(4-fluoro-2-iodophenyl)-1H-pyrazole-4-carbonitrile(200 mg, 0.390 mmol) and tributyl(1-ethoxyvinyl)stannane (159 mg, 0.440mmol) in toluene (10 mL) was added Pd(PPh₃)₂Cl₂ (14 mg, 0.02 mmol) at25° C. The mixture was degassed with N₂ for three times and then stirredat 100° C. for 16 h. The mixture was concentrated under reduced pressureto give crude5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(2-(1-ethoxyvinyl)-4-fluorophenyl)-1H-pyrazole-4-carbonitrile(175 mg, yield: 100%) as a brown solid without further purification forthe next step. LC/MS (ESI) m/z: 444 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(2-(1-ethoxyvinyl)-4-fluorophenyl)-1H-pyrazole-3-carbonitrile

m/z (ESI): 444 [M + H]5-bromo-4-((1-(2-(1-ethoxyvinyl)-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-ethyl-1H-pyrazole

m/z (ESI): 487 [M + H]5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-1-(2-(1-ethoxyvinyl)-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole

m/z (ESI): 445 [M + H]

Synthesis of2-(5-(1-ethyl-1H-pyrazole-4-carbonyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorobenzaldehyde

To a solution of(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone(1.84 g, 4.98 mmol) in THF (20 mL) and H₂O (5 mL) was added cone. HCl(5.0 mL) in one portion at 0° C. The resulting solution was stirred at20° C. for 1 h. Then the reaction mixture was quenched with sat. aq.NaHCO₃ and partitioned between EtOAc and water. The organic layer wasseparated, washed with sat. NH₄Cl and brine, dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (50 of EtOAc in PE, V/V) to give2-(5-(1-ethyl-1H-pyrazole-4-carbonyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorobenzaldehyde(650 mg, 40% yield) as a yellow solid. TLC: R_(f)=0.5 (PE/EA=1:1), LC/MSEST (m/z): 327 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

2-(5-(5-bromo-1-ethyl-1H-pyrazole-4-carbonyl)-1H-pyrazol-1-yl)-5-fluorobenzaldehyde

m/z (ESI): 391 [M + H]2-(5-(5-bromo-1-ethyl-1H-pyrazole-4-carbonyl)-4-fluoro-1H-pyrazol-1-yl)-5-fluorobenzaldehyde

m/z (ESI): 409 [M + H]2-(5-(1-ethyl-1H-pyrazole-4-carbonyl)-3-fluoro-1H-pyrazol-1-yl)-5-fluorobenzaldehyde

m/z (ESI): 331 [M + H]

Synthesis of1-(2-acetyl-4-fluorophenyl)-5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-4-carbonitrile

To a solution of5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-(2-(1-ethoxyvinyl)-4-fluorophenyl)-1H-pyrazole-4-carbonitrile(200 mg, 0.390 mmol) in THF (2 mL) was added aq. HCl (1 M, 2.0 mL) at25° C. After stirring at 30° C. for 2 h, the mixture was neutralized topH 8 with sat. aq. NaHCO₃ and then extracted with EtOAc twice. Thecombined extracts were washed with H₂O and brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography on silica gel (0→35% EA in PE) to give1-(2-acetyl-4-fluorophenyl)-5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-4-carbonitrile(100 mg, yield: 53%) as a yellow oil. LC/MS (ESI) m/z: 416 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

1-(2-acetyl-4-fluorophenyl)-5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carbonitrile

m/z (ESI): 416 [M + H]1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-one

m/z (ESI): 459 [M + H]1-(2-(5-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-one

m/z (ESI): 417 [M + H]

Synthesis of(1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

To a stirred solution of(3-chloro-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)(l-ethyl-1H-pyrazol-4-yl)methanol(19.1 g, 54.5 mmol) and imidazole (7.40 g, 109 mmol) in THF (200 mL) wasadded a Solution of tert-butyl(chloro)dimethylsilane (7.50 g, 49.6 mmol)dropwise in THF (20 mL) at 0° C. After addition, the reaction wasstirred at r.t. for 18 h. The mixture was concentrated and purified byflash chromatography (10→50% EtOAc in PB) to give[1-(2-{[(tert-butyldimethylsilyl)oxy]methyl}-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl](1-ethyl-1H-pyrazol-4-yl)methanol(20.5 g, 8100 yield) as a yellow oil. LC/MS (ESI) (m/z): 465 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

[1-(2-{[(tert-butyldimethylsilyl)oxy]methyl}-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl][1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methanol

m/z (ESI): 492 [M + H]2-[(tert-butyldimethylsilyl)oxy]-1-[5-fluoro-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)phenyl]ethan-1-ol

m/z (ESI): 467 [M + H]3-{2-└((tert-butyldimethylsilyl)oxy┘-1-└(5-fluoro-2-(1H-imidazol-2-yl)phenyl┘ethoxy}-2-nitropyridine

m/z (ESI): 459 [M + H]

Synthesis of(1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone

To a stirred solution of[1-(2-{[(tert-butyldimethylsilyl)oxy]methyl}-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl](1-ethyl-1H-pyrazol-4-yl)methanol(20.5 g, 44.2 mmol) in DCM (250 mL) was added MnO₂ (40.0 g, 460 mmol).After addition, the mixture was stirred at r.t. for 2 h. The reactionwas filtered and concentrated to give(1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone(20.4 g, 99% yield) as a yellow solid. LC/MS (ESI) (m/z): 463 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

4-[1-(2-{[(tert-butyldimethylsilyl)oxy]methyl}-4-fluorophenyl)-3-chloro-1H-pyrazole-5-carbonyl]-1-(cyclopropylmethyl)-1H-1,2,3-triazole

m/z (ESI): 490 [M + H]

Synthesis of(3-chloro-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone

To a stirred solution of(1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone(20.4 g, 44.1 mmol) in THF (150 mL) was added TBAF (135 mL, 135 mmol, 1M in THF) at r.t. The mixture was stirred at 70° C. for 1.5 h. Thereaction was poured into water (200 mL) and extracted with EtOAc (100mL×2). The combined organic layers were washed with brine (200 mL),dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby flash chromatography (10-50% EtOAc in PE) to give(3-chloro-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone(12.6 g, 82%) as a yellow oil. LC/MS (ESI) (m/z): 349 [M+H]⁺.

Synthesis of(R)-4-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-5-((1-ethyl-1H-pyrazol-4-yl)methyl)oxazole

To a solution of(R)-1-(2-(5-((1-ethyl-1H-pyrazol-4-yl)methyl)oxazol-4-yl)-5-fluorophenyl)ethan-1-ol(247 mg, 0.780 mmol) in THF (4 mL), was added NaH (47 mg, 1.2 mmol, 60%,in mineral oil) in portions at 0° C. The resulting mixture was stirredat 0° C. for 30 min, then 5-bromo-3-fluoro-2-nitropyridine (208 mg,0.940 mmol) was added. The reaction as heated to 80° C. and stirring wascontinued for 3 h. The mixture was cooled to r.t., quenched with water(5 mL), and extracted with EA (3×5 mL). The combined organic phases werewashed with sat. aq. NH₄Cl (5 mL) and brine (5 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified byflash chromatography (0→40% EtOAc in PE) to give(R)-4-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-5-((1-ethyl-1H-pyrazol-4-yl)methyl)oxazol(144 mg, 36% yield) as a yellow gum. LC/MS ESI (m/z): 516 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(R)-4-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-5-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)-2-methylthiazole

m/z (ESI): 560 [M + H]

Synthesis of5-bromo-3-[1-(2-{4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,2-oxazol-3-yl}-5-fluorophenyl)ethoxy]-2-nitropyridine

To a stirred solution of1-(2-{4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,2-oxazol-3-yl}-5-fluorophenyl)ethan-1-ol(113 mg, 0.358 mmol) in THF (4 mL) was added NaH (22 mg, 0.54 mmol, 60%in mineral oil) at 0° C. under N₂. After stirring at 0° C. for 50 min, asolution of 5-bromo-3-fluoro-2-nitropyridine (87 mg, 0.39 mmol) in THF(4 mL) was added dropwise at 0° C. The ice bath was removed, and thereaction was stirred at 25° C. for 12 h. The mixture was quenched withsat. aq. NH₄Cl (10 mL), extracted with EtOAc (10 mL), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelchromatography (50% EtOAc in PE) to give5-bromo-3-[1-(2-{4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1,2-oxazol-3-yl}-5-fluorophenyl)ethoxy]-2-nitropyridine(83 mg, 45% yield) as a yellow oil. LC/MS (ESI) m/z: 516 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(R)-5-bromo-3-(1-(2-(4-((5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-5-chloro-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): [M + H] 6815-bromo-3-(1-(2-(1-((5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 615 [M + H]5-bromo-3-(1-(2-(3-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl)-5-fluoropyridin-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 545 [M + H](R)-5-bromo-3-(1-(2-(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 563 [M + H](R)-5-bromo-3-(1-(2-(5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 563 [M + H](R)-5-((4-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2-methylthiazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 557 [M + H](R)-5-bromo-3-(1-(2-(4-((3-chloro-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 599 [M + H]5-bromo-3-[(1R)-1-[2-(4-{[1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl]methyl}-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl]ethoxy]-2-nitropyridine

m/z (ESI): 579 [M + H]5-bromo-3-[(1R)-1-{2-[1-(difluoromethyl)-4-[(1-ethyl-1H-pyrazol-4-yl)methyl]-1H-pyrazol-3-yl]-5-fluorophenyl}ethoxy]-2-nitropyridine

m/z (ESI): 565 [M + H](R)-5-bromo-3-(1-(2-(4-((1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 597 [M + H](R)-5-((4-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)thiazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 543 [M + H](R)-5-bromo-3-(1-(2-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 555 [M + H](R)-5-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-5-fluoropyridin-3-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 555 [M + H](R)-3-((1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-1-isopropyl-1H-pyrazole-5-carbonitrile

m/z (ESI): 554 [M + H](R)-5-bromo-3-(1-(2-(5-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 592 [M + H]5-bromo-3-[(lR)-1-[2-(5-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl]ethoxy]-2-nitropyridine

m/z (ESI): 610 [M + H]5-bromo-3-[(lR)-1-[2-(4-{[3-chloro-1-(cyclopropylmethyl)-1H-pyrazol-4-yl]methyl}-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl]ethoxy]-2-nitropyridine

m/z (ESI): 589 [M + H](R)-5-bromo-3-(1-(2-(3-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)pyridin-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 566 [M + H](R)-5-bromo-3-(1-(2-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 569 [M + H](R)-5-bromo-3-(1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)methyl)-6-methoxypyridin-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 556 [M + H](R)-2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-3-((1-ethyl-1H-pyrazol-4-yl)methyl)-4-methoxypyridine

m/z (ESI): 556 [M + H](R)-5-bromo-3-(1-(2-(3-((4-(cyclopropylmethyl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 552 [M + H](R)-5-bromo-3-(1-(2-(4-((1,3-diethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 557 [M + H](R)-5-bromo-3-(1-(2-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-(difluoromethyl)-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 591 [M + H]5-bromo-3-[(lR)-1-{5-fluoro-2-[1-methyl-4-({1-[(1-methylcyclopropyl)methyl]-1H-pyrazol-4-yl}methyl)-1H-pyrazol-3-yl]phenyl}ethoxy]-2-nitropyridine

m/z (ESI): 569 [M + H]1-((4-(2-(1-(5-bromo-2-nitropyridin-3-yloxy)ethyl)-4-fluorophenyl)thiazol-5-yl)methyl)-1H-imidazole-4-carbonitrile

m/z (ESI): 529 [M + H]1-((4-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2-methylthiazol-5-yl)methyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 543 [M + H](1-(2-(((5-bromo-2-nitropyridin-3-yl)oxy)methyl)-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone

m/z (ESI): 549 [M + H](1-(2-((5-bromo-2-nitropyridin-3-yloxy)methyl)-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

m/z (ESI): 585 [M + H]5-bromo-3-[(2-{3-chloro-5-[1-(cyclopropylmethyl)-1H-1,2,3-triazole-4-carbonyl]-1H-pyrazol-1-yl}-5-fluorophenyl)methoxy]-2-nitropyridine

m/z (ESI): 576 [M + H]4-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-5-((4-(difluoromethyl)-1H-pyrazol-1-yl)methyl)-2-methylthiazole

m/z (ESI): 568 [M + H]5-bromo-3-(1-(2-(3-bromo-5-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 593 [M + H]5-bromo-3-[(lR)-1-(2-{5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-methoxy-1H-pyrazol-1-yl}-5-fluorophenyl)ethoxy]-2-nitropyridine

m/z (ESI): 545 [M + H]5-bromo-3-[(2-{5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-methyl-1,3-thiazol-4-yl}-5-fluorophenyl)methoxy]-2-nitropyridine

m/z (ESI): 532 [M + H]5-bromo-3-[1-(2-{4-┌(3-ethyl-1,2-oxazol-5-yl)methyl┐-4H-1,2,4-triazol-3-yl}-5-fluorophenyl)ethoxy]-2-nitropyridine

m/z (ESI): 517 [M + H]5-((1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 540 [M + H]5-bromo-3-((2-(4-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 555 [M + H]5-bromo-3-((2-(4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorobenzyl)oxy)-2-nitropyridine

m/z (ESI): 541 [M + H]1-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-4-carbonitrile

m/z (ESI): 526 [M + H]3-{2-[(tert-butyldimethylsilyl)oxy]-1-[5-fluoro-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)phenyl]ethoxy}-2-nitropyridine

m/z (ESI): 589 [M + H](R)-5-bromo-3-(1-(2-(4-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 543 [M + H](R)-5-bromo-3-(1-(2-(4-((3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 579 [M + H](R)-5-bromo-3-(1-(2-(4-((3-(cyclopropylmethyl)-1-methyl-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 569 [M + H]

Synthesis of(1-(2-(((5-bromo-2-nitropyridin-3-yl)oxy)methyl)-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol

The mixture of(1-ethyl-1H-pyrazol-4-yl)(1-(4-fluoro-2-(hydroxymethyl)phenyl)-3-methyl-1H-pyrazol-5-yl)methanol(320 mg, 0.99 mmol), 5-bromo-3-fluoro-2-nitropyridine (241 mg, 1.09mmol), Cs₂CO₃ (968 mg, 2.97 mmol) and dry THF (15 mL) was stirred at 60°C. for 16 h. The reaction mixture was filtered through celite and thefiltrate was partitioned between EtOAc and water. The organic layer wasseparated, dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by flash chromatography (15→40% EtOAc inPE) to give(1-(2-(((5-bromo-2-nitropyridin-3-yl)oxy)methyl)-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanol(210 mg, 40% yield) as a yellow solid. TLC: R_(f)=0.3 (PE/EA=1/1). LC/MSESI (m/z): 531 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

5-bromo-3-(1-(2-(5-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-1,2,3-triazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 594 [M + H]5-bromo-3-(1-(2-(1-((5-bromo-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

m/z (ESI): 629 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazol-5-yl)methanone

m/z (ESI): 607 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(2-(((5-bromo-2-nitropyridin-3-yl)oxy)methyl)-4-fluorophenyl)-1H-pyrazol-5-yl)methanol

m/z (ESI): 595 [M + H](5-bromo-1-ethyl-1H-pyrazol-4-yl)(1-(2-(((5-bromo-2-nitropyridin-3-yl)oxy)methyl)-4-fluorophenyl)-4-fluoro-1H-pyrazol-5-yl)methanol

m/z (ESI): 613 [M + H](1-(2-(1-(5-bromo-2-nitropyridin-3-yloxy)ethyl)-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone

m/z (ESI): 563 [M + H]

Synthesis of(1R)-1-(2-{5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-methoxy-1H-pyrazol-1-yl}-5-fluorophenyl)ethan-1-ol

A mixture of1-{2-[(1R)-1-(benzyloxy)ethyl]-4-fluorophenyl}-5-[1-ethyl-1H-pyrazol-4-yl)methyl]-3-methoxy-1H-pyrazole(350 mg, 0.81 mmol), and Pd/C (30 mg, 1000 wt.) in MeOH (20 mL) wasstirred for 12 h at 50° C. under an H₂ atmosphere. The reaction mixturewas cooled and then filtered. The filtrate was concentrated underreduced pressure and the residue was purified by flash columnchromatography on silica gel (0→80% EtOAc in PE) to give(1R)-1-(2-{5-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-methoxy-1H-pyrazol-1-yl}-5-fluorophenyl)ethan-1-ol(220 mg, 79%) as a colorless oil. LC/MS (ESI): m/z=345 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(R)-1-(2-(3-(difluoromethyl)-5-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 365 [M + H](R)-1-(2-(5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 409 [M + H](R)-1-(2-(5-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 392 [M + H](R)-1-(2-(5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 405 [M + H](R)-1-(2-(5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 391 [M + H](R)-1-(2-(3-(difluoromethyl)-5-((1-ethyl-3-methoxy-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 395 [M + H](R)-1-(2-(5-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methyl)-3-methoxy-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 372 [M + H](2-(5-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)methanol

m/z (ESI): 377 [M + H](2-(5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)methanol

m/z (ESI): 391 [M + H]

Synthesis of(R)-4-((1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-3-methoxy-1H-pyrazol-5-yl)methyl)-1-(cyclopropylmethyl)-1H-1,2,3-triazole

To a stirred solution of(1-(2-((1R)-1-(benzyloxy)ethyl)-4-fluorophenyl)-3-methoxy-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methanol(652 mg, 1.37 mmol) in DCM (10 mL) were added TFA (1.56 g, 13.7 mmol)and TES (1.58 g, 13.7 mmol) at r.t. The reaction was stirred at 45° C.for 12 h, concentrated, and the residue was diluted with EtOAc (10 mL).The resulting solution was washed with sat. NaHCO₃ (10 mL) and brine (15mL), dried over anhydrous Na₂SO₄ and concentrated to dryness. Theresidue was purified by column chromatography on silica gel (PE:EA=2:1)to give(R)-4-((1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-3-methoxy-1H-pyrazol-5-yl)methyl)-1-(cyclopropylmethyl)-1H-1,2,3-triazole(541 mg, 86% yield) as a yellow oil. LC/MS (ESI) (m/z): 462.2 [M+H]⁺.

Synthesis of5-(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-pyrazole-5-carbonyl)-1H-pyrazole-3-carbonitrile

To a solution of hydroxyl ammonium hydrochloride (0.250 g, 3.60 mmol) inEtOH (10 mL) was added sodium acetate (0.300 g, 3.66 mmol) and thereaction was stirred at r.t. for 30 min. To this mixture was then addeda solution of5-(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-pyrazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbaldehyde(1.00 g, 2.05 mmol) in EtOH (10 mL), and stirring was continued at r.t.for 1 h. The reaction mixture was poured into ice water (50 mL), andthen extracted with EA (2×30 mL). The combined organic phases werewashed with water (20 mL) and brine (20 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo to give the crude aldoxime.To this residue in DCM (10 mL) was added SOCl₂ (0.98 g, 8.2 mmol) at 0°C. and the reaction was stirred at r.t. for 1 h. The mixture was pouredinto ice water (10 mL), and then extracted with EA (2×5 mL). Thecombined organic phases were washed with brine (10 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by prep-TLC (25% EtOAc in PE) to give5-(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-pyrazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile(0.55 g, 55% yield over 2 steps) as a yellow oil. LC/MS ESI (m/z): 484[M+H]⁺.

To a solution of5-(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-pyrazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile(600 mg, 1.24 mmol) in THF (5 mL), was added TBAF (1.0 M in THF, 5.00mL, 5.00 mmol) and the reaction was stirred at 70° C. for 3 h. Themixture was concentrated in vacuo, and the residue was purified by flashchromatography (0→25% EtOAc in PE) to give5-(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-pyrazole-5-carbonyl)-1H-pyrazole-3-carbonitrile(350 mg, 80%) as a white solid. LC/MS ESI (m/z): 354 [M+H]⁺.

Synthesis of(R)-5-((3-chloro-1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

To a solution of5-((3-chloro-1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(600 mg, 1.21 mmol) and DIPEA (1.0 mL, 6.05 mmol) in DCM (20 mL) wasadded MsCl (415 mg, 3.63 mmol) at 0° C. The reaction mixture was stirredat r.t. for 2 h. The reaction mixture was slowly poured into ice-waterand extracted with DCM twice. The combined organic layers were washedwith brine, dried (MgSO₄) and concentrated to afford crude(3-chloro-1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)(3-cyano-1-methyl-1H-pyrazol-5-yl)methylmethanesulfonate (680 mg, 98%) as a yellow oil.

To a solution of(3-chloro-1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)(3-cyano-1-methyl-1H-pyrazol-5-yl)methylmethanesulfonate (680 mg, 1.18 mmol) in EA (20 mL) were added Pd/C (126mg, 10% wt.). The reaction mixture was degassed with H₂ three times.Then the reaction mixture was stirred at r.t. under H₂ (15 psi)overnight. The reaction mixture was filtered through celite and thefiltrate was concentrated. The residue was purified by flashchromatography (silica gel, 0→15% ethyl acetate in petroleum ether) togive(R)-5-((3-chloro-1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(330 mg, 58%) as a yellow oil. LC/MS ESI (m/z): 480 [M+H]⁺.

Synthesis of5-bromo-3-(1-(2-(3-chloro-5-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine

To a solution of(1-(2-(1-(5-bromo-2-nitropyridin-3-yloxy)ethyl)-4-fluorophenyl)-3-chloro-1H-pyrazol-5-yl)(1-ethyl-1H-pyrazol-4-yl)methanone(390 mg, 0.69 mmol) in TFA (5 mL) was added Et₃SiH (1.1 mL, 6.9 mmol).The resulting mixture was stirred at 25° C. for 1 h. After concentrationin vacuo, the residue was partitioned between DCM (10 mL) and sat. aq.NaHCO₃ (10 mL), The organic layer was separated, washed with brine (10mL) and concentrated in vacuo to give crude5-bromo-3-(1-(2-(3-chloro-5-((1-ethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine(300 mg, 7%) as a white solid. LC/MS (ESI): m/z=549 [M+H]⁺.

Synthesis of(R)-1-(2-(5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-methoxy-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

To a solution of(R)-1-(2-(1-(benzyloxy)ethyl)-4-fluorophenyl)-5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-methoxy-1H-pyrazole(610 mg, 1.24 mmol) in MeOH (10 mL) was added Pd/C (100 mg, 10% wt) atr.t. The mixture was thrice degassed under H₂ and stirred at r.t. for 12h under an H₂ atmosphere. The mixture was filtered, and the filtrate wasconcentrated to dryness. The residue was purified by columnchromatography on silica gel (PE:EA=1:1) to give(R)-1-(2-(5-((1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl)methyl)-3-methoxy-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol(228 mg, 39% yield) as a yellow oil. LC/MS (ESI) (m/z): 385.2 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(R)-1-(2-(5-((3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)methyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 415 [M + H]

Synthesis of(R)-5-((3-chloro-1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

To a solution of(R)-5-((3-chloro-1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(330 mg, 0.680 mmol) in DCM (10 mL) was added TFA (1 mL) at r.t. and thereaction mixture was stirred at r.t. for 30 min. Then the reactionmixture was slowly poured into sat. NaHCO₃ and extracted with DCM twice.The combined organic layers were washed with brine, dried (MgSO₄) andconcentrated. The residue was purified by flash column chromatography(silica gel, 0→30% EtOAc in petroleum ether) to afford(R)-5-((3-chloro-1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(215 mg, 87%) as a white solid. LC/MS ESI (m/z): 360 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(1R)-1-(2-{5-[(1-ethyl-1H-1,2,3-triazol-4-yl)methyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-5-fluorophenyl)ethan-1-ol

m/z (ESI): 384 [M + H](R)-5-((1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 394 [M + H](R)-1-(2-(3-chloro-5-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-pyrazol-1-yl)-5-fluorophenyl)ethan-1-ol

m/z (ESI): 376 [M + H](R)-5-((3-(difluoromethyl)-1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

m/z (ESI): 376 [M + H]

Synthesis of1-{2-[(1R)-1-(benzyloxy)ethyl]-4-fluoropheny}-5-{[3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol-5-yl]methyl}-3-(difluoromethyl)-1H-pyrazole

To a solution of(1-{2-[(1R)-1-(benzyloxy)ethyl]-4-fluorophenyl}-3-(difluoromethyl)-1H-pyrazol-5-yl)[3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol-5-yl]methanol(0.45 g, 0.86 mmol) in DCM (8 mL) was added SOCl₂ (0.20 mL, 2.8 mmol)dropwise at 0° C. The mixture was stirred r.t. for 1 h, and thenconcentrated. The residue was dissolved in acetic acid (4 mL) and thenZn powder (0.50 g, 7.6 mmol) was added at 0° C. The mixture was stirredat r.t. for 2 h, and then filtered. The filtrate was concentrated, theresidue was diluted with sat. aq. NaHCO₃, and then extracted with EA (20mL×2). The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated. The residue was purified by columnchromatography on silica gel (25% EtOAc in PE) to give1-{2-[(1R)-1-(benzyloxy)ethyl]-4-fluorophenyl}-5-{[3-(2,2-difluoroethyl)-1-methyl-1H-pyrazol-5-yl]methyl}-3-(difluoromethyl)-1H-pyrazole(0.35 g, 76% yield) as a colorless oil. LC/MS (ESI) m/z: 505[M+H]⁺.

Synthesis of(3-chloro-1-(4-fluoro-2-(((4-methoxybenzyl)oxy)methyl)phenyl)-1H-pyrazol-5-yl)(3-cyano-1-methyl-1H-pyrazol-5-yl)methylmethanesulfonate

To a solution of5-((3-chloro-1-(4-fluoro-2-(((4-methoxybenzyl)oxy)methyl)phenyl)-1H-pyrazol-5-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(550 mg, 1.10 mmol) and DIPEA (442 mg, 3.40 mmol) in DCM (8 mL) wasadded MsCl (261 mg, 2.20 mmol) under the atmosphere of N₂ at 0° C. Afterstirring at 0° C. for 2 h, the reaction was extracted with EA. Thecombined organic phase was washed with sat. aq. NaCl, dried overanhydrous Na₂SO₄, filtered and concentrated to give crude(3-chloro-1-(4-fluoro-2-(((4-methoxybenzyl)oxy)methyl)phenyl)-1H-pyrazol-5-yl)(3-cyano-1-methyl-1H-pyrazol-5-yl)methylmethanesulfonate (700 mg) as a yellow oil. LC/MS (ESI) m/z: 560 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

(1-ethyl-1H-1,2,3-triazol-4-yl)(1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylmethanesulfonate

m/z (ESI): 598 [M + H](3-chloro-1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methylmethanesulfonate

m/z (ESI): 590 [M + H]

Synthesis of3-(1-(4-fluoro-2-formylphenyl)-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile

To a solution of3-(1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile(155 mg, 0.420 mmol) in acetone (3 mL) was added ferric chloride (21 mg,0.13 mmol), then the mixture was stirred at r.t. for 4 h. After 4 h, thereaction mixture was concentrated in vacuo to give the crude product.The crude product was purified by flash chromatography (0-40% EtOAc inPE) to give3-(1-(4-fluoro-2-formylphenyl)-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile(98 mg, 72%) as a white solid. LC/MS ESI (m/z): 324 [M+H]⁺.

Synthesis of(R)-5-((1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

To a solution of5-((1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(800 mg, 1.51 mmol) and DIPEA (976 mg, 7.55 mmol) in DCM (20 mL) wasadded MsCl (519 mg, 4.53 mmol) at 0° C. The reaction mixture was stirredat r.t. for 2 h, and then slowly poured into ice-water and extractedtwice with DCM. The combined organic layers were washed with brine,dried over anhydrous MgSO₄ and concentrated to afford crude(3-cyano-1-methyl-1H-pyrazol-5-yl)(1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylmethanesulfonate (900 mg, 98%) as a yellow oil.

To a solution of(3-cyano-1-methyl-1H-pyrazol-5-yl)(1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylmethanesulfonate (900 mg, 1.48 mmol) in EA (20 mL) was added Pd/C (100mg, 0.94 mmol, 10% wt.). The mixture was degassed with H₂ three timesand stirred at r.t. under H₂ (15 psi) overnight. The mixture wasfiltered through celite and the filtrate was concentrated. The residuewas purified by flash column chromatography (silica gel, 0→20% ethylacetate in petroleum ether) to give(R)-5-((1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(350 mg, 46%) as a yellow oil. LC/MS ESI (m/z): 514 [M+H]⁺.

Synthesis of(1R)-1-[2-(5-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl]ethan-1-ol

To a solution of[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl](1-{4-fluoro-2-[(1R)-1-[(4-methoxyphenyl)methoxy]ethyl]phenyl}-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol(400 mg, 0.730 mmol) in DCM (10 mL) was added TEA (0.10 mL, 0.73 mmol)and MsCl (84 mg, 0.73 mmol) at 0° C. The reaction was stirred for 1 h atr.t. The mixture was diluted with water (10 mL) and extracted with DCM(3×10 mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. The residue was dissolved in EtOAc(20 mL) and to this solution was added Pd/C (40 mg, 10% wt.). Themixture was stirred under 1 atm. of H₂ at r.t. overnight. The reactionmixture was filtered, and the filtrate was concentrated under reducedpressure. The residue was purified by flash column chromatography (0→5%MeOH in DCM) to give(1R)-1-[2-(5-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-3-(trifluoromethyl)-1H-pyrazol-1-yl)-5-fluorophenyl]ethan-1-ol(75 mg, 25%) as a colorless oil. LC/MS (ESI) (m/z): 410 [M+H]⁺.

Synthesis of5-((3-chloro-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile

A solution of5-((3-chloro-1-(4-fluoro-2-(((4-methoxybenzyl)oxy)methyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(150 mg, 0.320 mmol) in DCM (5 mL) and TFA (0.5 mL) was stirred at 25°C. for 0.5 h. The mixture was diluted with NaHCO₃ and EtOAc. The layerswere separated, and the organic phase was washed with H₂O, brine. Theorganic layer was dried over anhydrous Na₂SO₄, filtered, After andconcentrated under vacuum. The residue was purified by flashchromatography (silica gel, 0-40% EA in PE) to give5-((3-chloro-1-(4-fluoro-2-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-3-carbonitrile(110 mg, 99% yield) as a yellow oil. LC/MS (ESI) m/z: 346 [M+H]⁺.

The following intermediates were synthesized using a similarexperimental protocol:

2-[5-fluoro-2-(1H-imidazol-2-yl)phenyl]-2-[(2-nitropyridin-3-yl)oxy]ethan-1-ol

m/z (ESI): 345 [M + H]

Synthesis of(R)-4-((3-chloro-1-(4-fluoro-2-(1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-(cyclopropylmethyl)-1H-1,2,3-triazole

To a solution of crude(3-chloro-1-(4-fluoro-2-((R)-1-((4-methoxybenzyl)oxy)ethyl)phenyl)-1H-pyrazol-5-yl)(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methylmethanesulfonate (690 mg, 1.17 mmol) in DCM (8 mL) were added Pd/C (100mg, 10% wt.) and EtOAc (80 mL). The resulting mixture was degassed withH2 three times and then stirred at 40° C. under 1 atm of H2 overnight.The mixture was filtered through celite, and the filtrate wasconcentrated and purified by flash column chromatography to afford(R)-4-((3-chloro-1-(4-fluoro-2-(1-(4-methoxybenzyloxy)ethyl)phenyl)-1H-pyrazol-5-yl)methyl)-1-(cyclopropylmethyl)-1H-1,2,3-triazole(250 mg, 43%) as a white solid. LC/MS (ESI) m/z: 496 [M+H]⁺.

Synthesis of(R)-3-((1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazole-5-carbonitrile

To a solution of(R)-3-((1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-Pyrazol-5-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile(230 mg, 0.40 mmol) in DCM (10 mL) was added TFA (5 mL) at r.t. Themixture was stirred at r.t. overnight, and then concentrated to affordcrude(R)-3-((1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazole-5-carbonitrile(180 mg, 98%) as a yellow oil. LC/MS ESI (m/z): 512 [M+H]⁺.

Compounds Example 1 (Method A)

-   -   Name:        (19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-NH₂        1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine    -   NMR: 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.51 (d, J=1.8 Hz,        1H), 7.30 (dd, J=10.7, 3.5 Hz, 2H), 7.12 (dd, J=8.5, 5.8 Hz,        1H), 7.00 (td, J=8.3, 2.7 Hz, 1H), 6.52 (d, J=1.6 Hz, 1H), 5.41        (m, 1H), 4.78 (s, 2H), 4.14 (qd, J=7.1, 1.5 Hz, 2H), 3.91 (s,        3H), 3.61 (d, J=16.1 Hz, 1H), 2.96 (d, J=15.7 Hz, 1H), 1.80 (d,        J=6.3 Hz, 3H), 1.41 (t, J=7.2 Hz, 3H).    -   LCMS: Method D; t_(R): 1.54 min; m/z: 419 [M+H]

To a solution of4-[(5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl]-3-iodo-1-methyl-1H-pyrazole(500 mg, 1.27 mmol) and5-bromo-3-[(1R)-1-[5-fluoro-2-(trimethylstannyl)phenyl]ethoxy]pyridin-2-amine(1.2 g, 2.53 mmol) in DMF (5 mL) was added AsPh₃ (775 mg, 2.53 mmol),CuI (4 mg, 0.03 mmol) and Pd₂(dba)₃ (116 mg, 0.127 mmol). The mixturewas stirred under N₂ at 100° C. overnight. The mixture was concentratedin vacuo to remove DMF, and the residue was purified by columnchromatography on silica gel (0→100% EtOAc in PE) to give(R)-5-bromo-3-(1-(2-(4-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine(300 mg, 41% yield) as a light-yellow solid. LC/MS ESI (m/z): 577[M+H]⁺.

To a mixture of5-bromo-3-[(1R)-1-(2-{4-[(5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl]-1-methyl-1H-pyrazol-3-yl}-5-fluorophenyl)ethoxy]pyridin-2-amine(250 mg, 0.432 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(329 mg, 1.3 mmol), Pd(OAc)₂ (19 mg, 0.086 mmol) and cataCXium A (62 mg,0.17 mmol) in MeOH (10 mL) was added a Solution of aq. NaOH (2.0 M, 0.43mL, 0.86 mmol). The mixture was twice flushed with N₂ and then stirredat 80° C. for 12 h. After cooling to r.t., the mixture was filteredthrough celite, and the filtrate was concentrated under reducedpressure. The residue was diluted with DCM (50 mL), washed with waterand brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. Theresidue was purified by prep-HPLC (Gemini 5 um C18 250*21.2 mm, MeCN inH₂O+0.1% FA) to give the target product (19 mg, 1% yield) as a whitesolid. LC/MS ESI (m/z): 419 [M+H]⁺.

The following compounds were prepared in a similar manner:

Example 2

16-fluoro-3,11,19-trimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),9,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.81 (dd, J = 10.3, 2.7 Hz, 1H), 7.59 (s, 1H), 7.55 (d, J = 1.7Hz, 1H), 7.37 (s, 1H), 7.27 (td, J = 8.4, 2.7 Hz, 1H), 7.20-7.14 (m,1H), 6.48 (d, J = 1.6 Hz, 1H), 6.13 (s, 2H), 5.08-4.95 (m, 1H), 3.75 (s,3H), 3.67 (d, J = 7.8 Hz, 1H), 3.58 (s, 3H), 2.62 (d, J = 15.4 Hz, 1H),1.79 (d, J = 6.2 Hz, 3H). LCMS Method C; t_(R): 0.98 min; m/z: 405 [M +H] Example 3

(20R)-3-ethyl-17-fluoro-20-methyl-21-oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23-undecaen-23- amine 1H NMR(400 MHz, DMSO) δ 8.55-8.50 (m, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.78 (s,1H), 7.69 (dd, J = 10.4, 2.7 Hz, 1H), 7.47-7.42 (m, 2H), 7.22 (dd, J =8.5, 5.9 Hz, 1H), 7.15 (td, J = 8.4, 2.7 Hz, 1H), 6.14 (s, 2H), 6.01 (d,J = 1.7 Hz, 1H), 5.12 (d, J = 4.4 Hz, 1H), 4.06 (tt, J = 13.9, 7.0 Hz,2H), 3.83 (d, J = 15.7 Hz, 1H), 3.09 (d, J = 15.5 Hz, 1H), 1.74 (d, J =6.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H). LCMS Method C; t_(R): 1.06 min;m/z: 416 [M + H] Example 4

(19R)-11-ethyl-16-fluoro-3,19-dimethyl-20-oxa- 3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),9,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.82 (dd, J = 10.3, 2.8 Hz, 1H), 7.58 (s, 1H), 7.55 (d, J =1.8 Hz, 1H), 7.40 (s, 1H), 7.27 (td, J = 8.3, 2.8 Hz, 1H), 7.19 (dd, J =8.5, 5.9 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 6.14 (s, 2H), 4.99 (dd, J =6.4, 2.1 Hz, 1H), 3.90 (dt, J = 14.3, 7.1 Hz, 1H), 3.75 (s, 3H), 3.71(dd, J = 13.8, 7.1 Hz, 1H), 3.55 (d, J = 15.6 Hz, 1H), 2.62 (d, J = 15.4Hz, 1H), 1.77 (d, J = 6.1 Hz, 3H), 1.25 (s, 3H). LCMS Method C; t_(R):1.07 min; m/z: 419 [M + H] Example 5

(19R)-3-cyclobutyl-16-fluoro-11,19-dimethyl-20-oxa- 3,4,10,11,23-pentaazapentacyclo19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),9,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.82 (dd, J = 10.3, 2.6 Hz, 1H), 7.68 (s, 1H), 7.38 (s, 1H),7.35 (d, J = 1.6 Hz, 1H), 7.25 (td, J = 8.4, 2.8 Hz, 1H), 7.16 (dd, J =8.5, 5.9 Hz, 1H), 6.46 (s, 1H), 6.14 (s, 2H), 5.10-4.97 (m, 1H),4.82-4.69 (m, 1H), 3.57 (s, 3H), 3.52 (s, 1H), 2.65 (d, J = 9.6 Hz, 1H),2.61 (d, J = 2.6 Hz, 1H), 2.47-2.38 (m, 2H), 2.12-2.04 (m, 1H), 1.78 (d,J = 6.2 Hz, 3H), 1.76-1.66 (m, 2H). LCMS Method C; t_(R): 1.18 min; m/z:445 [M + H] Example 6

(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20- oxa-5,6,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,4,8,11,13,15,17,21(25),22-decaene-4-carbonitrile 1H NMR (400MHz, DMSO) δ 7.85 (s, 1H), 7.76 (d, J = 10.2 Hz, 1H), 7.41 (s, 1H),7.15(d, J = 6.4 Hz, 2H), 6.33 (s, 1H), 6.28 (s, 2H), 5.47-5.37 (m, 1H), 5.32(d, J = 15.9 Hz, 1H), 4.26 (d, J = 15.7 Hz, 1H), 3.89 (s, 3H), 2.41-2.28(m, 2H), 1.73 (d, J = 6.2 Hz, 3H), 1.08 (t, J = 7.5 Hz, 3H). LCMS MethodF; t_(R): 1.08 min; m/z: 444 [M + H] Example 7

3-cyclobutyl-16-fluoro-10-methyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.68-7.61 (m, 2H), 7.56 (s, 1H), 7.31 (s, 1H), 7.21-7.15 (m,2H), 6.28 (s, 1H), 6.12 (s, 2H), 5.08 (dd, J = 26.2, 13.1 Hz, 2H),4.77-4.67 (m, 1H), 3.83 (s, 3H), 3.61 (d, J = 16.2 Hz, 1H), 2.73 (d, J =14.7 Hz, 1H), 2.70-2.64 (m, 1H), 2.44-2.36 (m, 2H), 2.10- 2.03 (m, 1H),1.77-1.65 (m, 2H). LCMS Method I; t_(R): 1.16 min; m/z: 431 [M + H]Example 8

3-ethyl-17-fluoro-21-oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0^(s),¹³.0¹⁴,^(1,9)]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23-undecaen-23- amine 1H NMR(400 MHz, DMSO) δ 8.51 (d, J = 3.5 Hz, 1H), 7.90 (d, J = 7.3 Hz, 1H),7.79 (s, 1H), 7.66 (dd, J = 10.1, 2.5 Hz, 1H), 7.50-7.40 (m, 2H),7.28-7.13 (m, 2H), 6.15 (s, 2H), 6.03 (s, 1H), 5.21 (d, J = 13.3 Hz,1H), 4.87 (d, J = 14.1 Hz, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.87 (d, J =15.6 Hz, 1H), 3.13 (d, J = 15.4 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H). LCMSMethod F; t_(R): 0.79 min; m/z: 402 [M + H]

Example 9 (Method B)

-   -   Name:        (19R)-22-amino-16-fluoro-10,19-dimethyl-20-oxa-5,6,10,11,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-1(24),2,4,8,11,13,15,17,21(25),22-decaene-3-carbonitrile    -   NMR: 1H NMR (400 MHz, DMSO) δ 8.16 (s, 1H), 7.83 (s, 1H), 7.71        (d, J=9.9 Hz, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.21-7.17 (m, 2H),        6.48-6.41 (m, 3H), 5.41-5.32 (m, 2H), 4.27 (d, J=15.8 Hz, 1H),        3.89 (s, 3H), 1.74 (d, J=6.2 Hz, 3H).    -   LCMS: Method D; t_(R): 1.72 min; m/z: 416 [M+H]

To a solution of1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-4-carbonitrile(600 mg, 1.92 mmol) and(R)-5-bromo-3-(1-(5-fluoro-2-(trimethylstannyl)phenyl)ethoxy)pyridin-2-amine(1.36 g, 2.87 mmol) in DMF (10 mL) was added AsPh₃ (586 mg, 1.92 mmol),CuI (4 mg, 0.02 mmol) and Pd₂(dba)₃ (150 mg, 0.190 mmol). The mixturewas thrice degassed with N₂ and then stirred at 100° C. overnight. Afterconcentration under reduced pressure, the residue was purified by columnchromatography on silica gel (0→100% EA in PE) to give(R)-1-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-4-carbonitrile(80 mg, 8.4%) as a pale-yellow solid. LC/MS ESI (m/z): 496 [M+H]⁺.

To a solution of(R)-1-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-4-carbonitrile(80 mg, 0.16 mmol) in 2-methyl-2-butanol (5 mL) was added KOAc (79 mg,0.80 mmol), cataCXium A (23 mg, 0.60 mmol) and Pd(OAc)₂ (7 mg, 0.03mmol). The mixture was thrice degassed with N₂ and then stirred in asealed tube at 120° C. overnight. After concentration under reducedpressure, the residue was purified by prep-HPLC (Gemini 5 um C18250*21.2 mm, MeCN in H₂O+0.1% FA) to give the target product (10 mg, 15%yield) as a white solid. LC/MS ESI (m/z): 416 [M+H]⁺.

The following compounds were prepared in a similar manner:

Example 10

(20R)-23-amino-17-fluoro-20-methyl-21-oxa-4,6,10,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2,4,8(13),9,11,14,16,18,22(26),23-undecaene-3- carbonitrile 1H NMR(400 MHz, DMSO) δ 8.80 (s, 1H), 8.65 (d, J = 4.9 Hz, 1H), 8.54 (s, 1H),7.73 (dd, J = 10.3, 2.3 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.37 (d, J =5.0 Hz, 1H), 7.26- 7.17 (m, 2H), 6.43 (s, 2H), 6.17 (d, J = 1.7 Hz, 1H),5.56 (d, J = 16.2 Hz, 1H), 5.20 (d, J = 4.6 Hz, 1H), 4.34 (d, J =16.1Hz, 1H), 1.82 (d, J = 6.2 Hz, 3H). LCMS Method C; t_(R): 1.03 min;m/z: 413 [M + H] Example 11

(20R)-23-amino-17-fluoro-20-methyl-21-oxa-4,6,11,24- tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2,4,8(13),9,11,14,16,18,22(26),23-undecaene-3- carbonitrile 1H NMR(400 MHz, DMSO) δ 8.73 (d, J = 5.2 Hz, 1H), 8.54 (s, 1H), 8.47 (s, 1H),7.75-7.70 (m, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 5.3 Hz, 1H),7.27-7.22 (m, 2H), 6.47 (s, 2H), 6.05 (d, J = 1.9 Hz, 1H), 5.49 (d, J =16.5 Hz, 1H), 5.17-5.09 (m, 1H), 4.30 (d, J = 16.2 Hz, 1H), 1.83 (d, J =6.3 Hz, 3H). LCMS Method C; t_(R): 0.96 min; m/z: 413 [M + H] Example 12

(20R)-23-amino-17-fluoro-20-methyl-21-oxa-4,6,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2,4,8(13),9,11,14,16,18,22(26),23-undecaene-3- carbonitrile 1H NMR(400 MHz, DMSO) δ 8.75-8.65 (m, 1H), 8.47 (s, 1H), 7.99 (d, J = 8.0 Hz,1H), 7.70 (dd, J = 10.3, 2.5 Hz, 1H), 7.66-7.52 (m, 2H), 7.21 (td, J =8.5, 2.5 Hz, 2H), 6.42 (s, iment2H), 6.09 (d, J = 1.7 Hz, 1H), 5.54 (d,J = 16.1 Hz, 1H), 5.15 (d, J = 4.7 Hz, 1H), 4.35 (d, J = 16.0 Hz, 1H),1.77 (d, J = 6.2 Hz, 3H). LCMS Method C; t_(R): 0.95 min; m/z: 413 [M +H] Example 13

(19R)-22-amino-16-fluoro-10,19-dimethyl-20-oxa- 4,6,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,4,8,11,13,15,17,21(25),22-decaene-3-carbonitrile 1H NMR (400MHz, DMSO) δ 8.28 (s, 1H), 7.94 (s, 1H), 7.70 (dd, J = 10.3, 2.3 Hz,1H), 7.55 (d, J = 1.7 Hz, 1H), 7.21-7.11 (m, 2H), 6.37 (s, 3H),5.42-5.30 (m, 2H), 4.01 (d, J = 15.8 Hz, 1H), 3.90 (s, 3H), 1.73 (d, J =6.2 Hz, 3H). LCMS Method C; t_(R): 0.93 min; m/z: 416 [M + H] Example 14

(20R)-23-amino-17-fluoro-20-methyl-21-oxa-5,6,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2,4,8(13),9,11,14,16,18,22(26),23-undecaene-3- carbonitrile 1H NMR(400 MHz, DMSO-d6) δ 8.62 (dd, J = 4.7, 1.4 Hz, 1H), 8.18 (s, 1H), 8.05(d, J = 7.2 Hz, 1H), 7.64 (dd, J = 10.3, 2.7 Hz, 1H), 7.58 (s, 1H), 7.49(dd, J = 8.0, 4.7 Hz, 1H), 7.23 (dd, J = 8.5, 5.8 Hz, 1H), 7.16-7.05 (m,1H), 6.45 (s, 2H), 6.09 (s, 1H), 5.55 (d, J = 16.1 Hz, 1H), 5.09 (d, J =4.5 Hz, 1H), 4.49 (d, J = 16.0 Hz, 1H), 1.70 (d, J = 6.2 Hz, 3H) LCMSMethod C; t_(R): 1.29 min; m/z: 413 [M + H] Example 15

(19R)-22-amino-16-fluoro-10,19-dimethyl-5,20-dioxa- 4,10,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13(18),14,16,21(25),22-decaene-3- carbonitrile 1H NMR(400 MHz, DMSO) δ 7.84 (s, 1H), 7.64 (d, J = 9.7 Hz, 1H), 7.61 (d, J =1.8 Hz, 1H), 7.23 (d, J = 7.4 Hz, 2H), 6.31-6.16 (m, 3H), 5.26 (d, J =4.9 Hz, 1H), 4.27 (d, J = 16.2 Hz, 1H), 3.88 (s, 3H), 3.31 (d, 1H), 1.73(d, J = 6.3 Hz, 3H). LCMS Method H; t_(R): 1.06 min; m/z: 417 [M + H]Example 16

(20R)-3-ethyl-10,17-difluoro-20-methyl-21-oxa- 4,5,6,12,24-pentaazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2,4,8(13),9,11,14,16,18,22(26),23-undecaen-23- amine 1H NMR (400MHz, DMSO) δ 8.72 (d, J = 2.7 Hz, 1H), 7.79-7.71 (m, 2H), 7.45 (d, J =1.8 Hz, 1H), 7.30 (dd, J = 8.6, 5.8 Hz, 1H), 7.22-7.16 (m, 1H), 6.28 (s,2H), 6.12 (s, 1H), 5.85 (d, J = 16.2 Hz, 1H), 5.24-5.15 (m, 1H), 4.53(d, J = 15.6 Hz, 1H), 2.62 (q, J = 7.5 Hz, 2H), 1.73 (d, J = 6.1 Hz,3H), 1.18 (t, J = 7.5 Hz, 3H). LCMS Method F; t_(R): 1.06 min; m/z: 435[M + H] Example 17

(20R)-3-(difluoromethyl)-10,17-difluoro-20-methyl-21- oxa-5,6,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2,4,8(13),9,11,14,16,18,22(26),23-undecaen-23- amine 1H NMR (400MHz, DMSO) δ 8.70 (d, J = 2.8 Hz, 1H), 7.94 (s, 1H), 7.91 (dd, J = 9.6,2.6 Hz, 1H), 7.76 (dd, J = 10.4, 2.7 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1H),7.27 (dd, J = 8.5, 5.8 Hz, 1H), 7.18 (td, J = 8.4, 2.7 Hz, 1H),7.04-6.71 (m, 1H), 6.36 (s, 2H), 6.21 (s, 1H), 5.54 (d, J = 16.1 Hz,1H), 5.22 (d, J = 8.0 Hz, 1H), 4.49 (d, J = 16.3 Hz, 1H), 1.74 (d, J =6.2 Hz, 3H). LCMS Method F; t_(R): 1.34 min; m/z: 456 [M + H] Example 18

(20R)-23-amino-17-fluoro-5,20-dimethyl-21-oxa- 4,6,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2,4,8(13),9,11,14,16,18,22(26),23-undecaene-3- carbonitrile 1H NMR(400 MHz, DMSO-d6) δ 8.71 (d, J = 4.4 Hz, 1H), 7.68 (s, 2H), 7.56 (t, J= 2.9 Hz, 2H), 7.38 (dd, J = 8.6, 5.7 Hz, 1H), 7.27-7.18 (m, 1H), 6.40(s, 2H), 6.07 (s, 1H), 5.50 (d, J = 16.7 Hz, 1H), 5.03 (s, 1H), 4.23 (d,J = 17.2 Hz, 1H), 2.64 (s, 3H), 1.74 (d, J = 6.2 Hz, 3H). LCMS Method F;t_(R): 0.88 min; m/z: 427 [M + H] Example 19

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-5,20-dioxa- 4,10,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.76 (s, 1H), 7.67 (d, J = 10.2 Hz, 1H), 7.44 (s, 1H), 7.19 (d,J = 7.1 Hz, 2H), 6.21 (s, 1H), 5.94 (s, 2H), 5.28 (d, J = 4.6 Hz, 1H),3.98 (d, J = 16.0 Hz, 1H), 3.89-3.83 (m, 3H), 3.15 (d, J = 15.7 Hz, 1H),2.78-2.64 (m, 1H), 2.63-2.54 (m, 1H), 1.71 (d, J = 6.3 Hz, 3H), 1.11 (t,J = 7.5 Hz, 3H). LCMS Method F; t_(R): 0.70 min; m/z: 420 [M + H]Example 20

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa- 3,4,5,10,11,23-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.68 (dd, J = 10.3, 2.5 Hz, 1H), 7.60 (s, 1H), 7.54 (d, J =1.9 Hz, 1H), 7.24-7.14 (m, 2H), 6.25 (d, J = 1.9 Hz, 1H), 6.22 (s, 2H),5.36 - 5.28 (m, 1H), 4.29 (qd, J = 7.1, 4.0 Hz, 2H), 3.93 (d, J = 15.6Hz, 1H), 3.85 (s, 3H), 2.96 (d, J = 15.4 Hz, 1H), 1.72 (d, J = 6.2 Hz,3H), 1.34 (t, J = 7.3 Hz, 3H). LCMS Method G; t_(R): 2.25 min; m/z: 420[M + H] Example 21

(19R)-22-amino-16-fluoro-5,10,19-trimethyl-20-oxa- 4,5,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, DMSO-d6) δ 7.89 (s, 1H), 7.66 (dd, J = 9.8, 1.3 Hz, 1H), 7.50 (d, J= 1.8 Hz, 1H), 7.25-7.17 (m, 2H), 6.27 (d, J = 2.0 Hz, 1H), 6.04 (s,2H), 5.29-5.18 (m, 1H), 4.14 (s, 3H), 4.04 (d, J = 16.5 Hz, 1H), 3.88(s, 3H), 3.03 (d, J = 16.4 Hz, 1H), 1.72 (d, J = 6.2 Hz, 3H). LCMSMethod G; t_(R): 2.88 min; m/z: 430 [M + H] Example 22

(19R)-3-(2,2-difluoroethyl)-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.70 (d, J = 8.2 Hz, 2H), 7.60 (s, 1H), 7.45 (d, J = 1.7 Hz,1H), 7.18-7.09 (m, 2H), 6.41 (dt, J = 55.3, 4.1 Hz, 1H), 6.27 (d, J =1.5 Hz, 1H), 6.23-6.11 (m, 2H), 5.42-5.24 (m, 1H), 4.56-4.31 (m, 2H),3.86 (s, 3H), 3.62 (d, J = 15.6 Hz, 1H), 2.72 (d, J = 14.5 Hz, 1H), 1.71(d, J = 6.2 Hz, 3H). LCMS Method F; t_(R): 0.89 min; m/z: 455 [M + H]Example 23

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa- 4,5,6,10,11,23-hexaazapcntacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸Jpentacosa-1(24),2,4,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.82 (s, 1H), 7.73 (d, J = 10.6 Hz, 1H), 7.41 (s, 1H),7.22-7.17 (m, 2H), 6.31 (s, 1H), 6.21 (s, 2H), 5.62 (d, J = 15.7 Hz,1H), 5.38 (d, J = 6.5 Hz, 1H), 4.26 (d, J = 15.7 Hz, 1H), 3.88 (s, 3H),2.56 (dd, J = 7.6, 2.7 Hz, 2H), 1.72 (d, J = 6.2 Hz, 3H), 1.14 (t, J =7.5 Hz, 3H). LCMS Method F; t_(R): 0.65 min; m/z: 420 [M + H] Example 24

(19R)-22-amino-16-fluoro-10,19-dimethyl-20-oxa- 4,5,6,10,11,23-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,4,8,11,13,15,17,21(25),22-decaene-3-carbonitrile 1H NMR (400MHz, DMSO) δ 7.92 (s, 1H), 7.70 (dd, J = 10.3, 2.3 Hz, 1H), 7.67 (d, J =1.9 Hz, 1H), 7.27-7.18 (m, 2H), 6.60 (s, 2H), 6.44 (d, J = 1.8 Hz, 1H),5.85 (d, J = 16.1 Hz, 1H), 5.40-5.32 (m, 1H), 4.43 (d, J = 15.9 Hz, 1H),3.90 (s, 3H), 1.75 (d, J = 6.3 Hz, 3H). LCMS Method F; t_(R): 1.09 min;m/z: 417 [M + H] Example 25

(20R)-23-amino-17-fluoro-20-methyl-21-oxa- 4,5,6,12,24-pentaazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2,4,8(13),9,11,14,16,18,22(26),23-undecaene-3- carbonitrile 1H NMR(400 MHz, DMSO) δ 8.73 (d, J = 3 .3 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H),7.70 (dd, J = 9.5, 2.2 Hz, 2H), 7.59 (dd, J = 8.0, 4.7 Hz, 1H), 7.36(dd, J = 8.5, 5.8 Hz, 1H), 7.24 (td, J = 8.4, 2.6 Hz, 1H), 6.68 (s, 2H),6.17 (s, 1H), 6.08 (d, J = 15.9 Hz, 1H), 5.15 (d, J = 4.1 Hz, 1H), 4.70(d, J = 16.1 Hz, 1H), 1.78 (d, J = 6.2 Hz, 3H). LCMS Method 1; t_(R):1.16 min; m/z: 414 [M + H] Example 26

(19R)-3-cyclobutyl-16-fluoro-10,19-dimethyl-5,20- dioxa-4,10,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.76 (s, 1H), 7.65 (d, J = 10.1 Hz, 1H), 7.30 (s, 1H), 7.19 (d,J = 7.1 Hz, 2H), 6.20 (s, 1H), 5.92 (s, 2H), 5.26 (q, J = 8.0 Hz, 1H),3.98 (d, J = 15.7 Hz, 1H), 3.88 (s, 3H), 3.14 (d, J = 15.8 Hz, 1H),2.40- 2.28 (m, 2H), 2.28-2.18 (m, 1H), 2.14-2.02 (m, 2H), 1.97 (dd, J =19.4, 7.2 Hz, 1H), 1.82 (qd, J = 12.2, 8.8 Hz, 1H), 1.71 (d, J = 6.3 Hz,3H). LCMS Method F; t_(R): 0.83 min; m/z: 446 [M + H] Example 27

(19R)-16-fluoro-10,19-dimethyl-3-(2,2,2-trifluoroethyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.76 (s, 1H), 7.70 (d, J = 9.9 Hz, 1H), 7.62 (s, 1H), 7.45 (d, J= 1.6 Hz, 1H), 7.14 (d, J = 7.2 Hz, 2H), 6.24 (s, 1H), 6.17 (s, 2H),5.32 (d, J = 4.6 Hz, 1H), 4.98 (dt, J = 17.4, 8.7 Hz, 1H), 4.88-4.75 (m,1H), 3.85 (s, 3H), 3.62 (d, J = 15.4 Hz, 1H), 2.71 (d, J = 15.4 Hz, 1H),1.71 (d, J = 6.2 Hz, 3H). LCMS Method F; t_(R): 0.76 min; m/z: 473 [M +H] Example 28

(19R)-9-chloro-3-ethyl-16-fluoro-10,19-dimethyl-20- oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.72 (d, J = 10.1 Hz, 1H), 7.60 (s, 1H), 7.39 (d, J = 1.8 Hz,1H), 7.16-7.11 (m, 2H), 6.35 (d, J = 1.7 Hz, 1H), 6.09 (s,2H),5.47 (dd,J = 6.4, 1.8 Hz, 1H), 3.98 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.63 (d, J= 15.7 Hz, 1H), 2.91 (d, J = 15.7 Hz, 1H), 1.72 (d, J = 6.2 Hz, 3H),1.26 (t, J = 7.2 Hz, 3H). LCMS Method F; t_(R): 0.66 min; m/z: 453 [M +H] Example 29

(19R)-3-(cyclopropylmethyl)-16-fluoro-10,19-dimethyl-20-oxa-3,4,5,10,11,23-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.68 (dd, J = 10.4, 2.5 Hz, 1H), 7.62 (s, 1H), 7.56 (d, J =1.8 Hz, 1H), 7.22-7.13 (m, 2H), 6.24 (d, J = 1.8 Hz, 1H), 6.21 (s, 2H),5.32 (qd, J = 6.3, 2.1 Hz, 1H), 4.15 (qd, J = 14.5, 7.0 Hz, 2H), 3.91(d, J = 15.5 Hz, 1H), 3.85 (s, 3H), 2.96 (d, J = 15.4 Hz, 1H), 1.71 (d,J = 6.2 Hz, 3H), 1.11 (ddt, J = 10.5, 7.5, 3.8 Hz, 1H), 0.49-0.38 (m,2H), 0.33-0.26 (m, 1H), 0.16 (dq, J = 9.7, 4.6 Hz, 1H). LCMS Method F;t_(R): 1.12 min; m/z: 446 [M + H] Example 30

3-ethyl-16-fluoro-10-methyl-5,20-dioxa-4,10,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,CDCl3) δ 7.51 (d, J = 1.2 Hz, 1H), 7.46 (s, 1H), 7.37 (dd, J = 9.3, 2.4Hz, 1H), 7.16 (dd, J = 8.4, 5.7 Hz, 1H), 7.07 (td, J = 8.2, 2.5 Hz, 1H),6.44 (s, 1H), 5.16 (q, J = 13.6 Hz, 2H), 4.93 (br s, 2H), 3.99 (d, J =15.7 Hz, 1H), 3.94 (s, 3H), 3.40 (d, J = 15.6 Hz, 1H), 2.83-2.61 (m,2H), 1.24 (t, J = 7.5 Hz, 3H). LCMS Method F; t_(R): 0.86 min; m/z: 406[M + H]

Example 31 (Method C)

-   -   Name:        (19R)-3-ethyl-16-fluoro-19-methyl-20-oxa-3,4,8,11,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-1(24),2(6),4,9,11,13,15,17,21(25),22-decaen-22-amine    -   NMR: 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.75 (dd, J=10.4,        2.8 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.38 (dd, J=8.6, 5.7 Hz,        1H), 7.26 (d, J=1.3 Hz, 1H), 7.21 (td, J=8.5, 2.9 Hz, 1H), 7.10        (d, J=1.2 Hz, 1H), 6.20 (s, 2H), 5.65 (s, 1H), 5.52 (q, J=7.4,        6.5 Hz, 1H), 5.01 (d, J=14.7 Hz, 1H), 4.19 (d, J=14.7 Hz, 1H),        4.14-3.99 (m, 2H), 1.74 (d, J=6.2 Hz, 3H), 1.28 (t, J=7.2 Hz,        3H).    -   LCMS: Method D; t_(R): 2.21 min; m/z: 405 [M+H]

To a solution of5-bromo-3-(1-(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine(560 mg, 0.94 mmol) in EtOH (10 mL) and water (2.5 mL) was added ironpowder (263 mg, 4.71 mmol) and NH₄Cl (504 mg, 9.42 mmol). The resultingmixture was stirred at 75° C. for 3 h. The reaction mixture wasconcentrated in vacuo, and the residue was purified by columnchromatography (silica gel, 0→50% EtOAc in PE) to give5-bromo-3-(1-(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine(421 mg, 79% yield) as a brown solid. LC/MS ESI (m/z): 563 [M+H]⁺.

To a solution of5-bromo-3-(1-(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine(338 mg, 0.600 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(456 mg, 1.80 mmol), Pd(OAc)₂ (27 mg, 0.12 mmol) and cataCXium A (54 mg,0.15 mmol) in MeOH (10 mL) was added a solution of aq. NaOH (2.0 M, 0.60mL, 1.2 mmol). The mixture was thrice degassed with N₂, and then stirredat 75° C. for 3 h. After cooling to r.t., the mixture was filtered, andthe filtrate was concentrated in vacuo. The residue was diluted with EA,washed with water and brine, dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The residue was purified by columnchromatography (silica gel, 0→90% EtOAc in PE) to give the racemicproduct as a white solid. This was further purified by chiral SFC(ChiralCel OJ 21.2 mm×250 mm 5 m, 20% MeOH=0.1% aq. NH₃ in CO₂, eutomert_(R): 4.90 min, distomer t_(R): 4.68 min) to obtain the eutomer as awhite solid (25 mg, yield: 10%). LC/MS ESI (m/z): 405 [M+H]⁺.

The following compounds were prepared in a similar manner:

Example 32

(19R)-3-ethyl-16-fluoro-11,19-dimethyl-20-oxa- 3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),9,13,15,17,21(25),22-decaen-22- amine 1H NMR (400MHz, DMSO-d6) δ 7.83 (dd, J = 10.3, 2.8 Hz, 1H), 7.63 (s, 1H), 7.47 (d,J = 1.8 Hz, 1H), 7.38 (s, 1H), 7.28-7.24 (m, 1H), 7.17 (dd, J = 8.5, 5.9Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 6.23 (s, 2H), 5.05 (dd, J = 6.4, 2.1Hz, 1H), 4.11-4.00 (m, 2H), 3.57 (s, 3H), 3.52 (s, 1H), 2.61 (d, J =15.4 Hz, 1H), 1.79 (d, J = 6.1 Hz, 3H), 1.26(t, J = 7.2 Hz, 3H). LCMSMethod C; t_(R): 0.97 min; m/z: 419 [M + H] Example 33

(19R)-3-ethyl-16-fluoro-19-methyl-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.83 (d, J = 10.2 Hz, 1H), 7.67 (d, J = 6.1 Hz, 2H), 7.49 (d,J = 1.6 Hz, 1H), 7.39- 7.34 (m, 1H), 7.27 (t, J = 7.1 Hz, 1H), 6.24 (d,J = 1.6 Hz, 1H), 6.19 (s, 2H), 6.03 (s, 1H), 5.14 (d, J = 6.9 Hz, 1H),4.07 (t, J = 6.9 Hz, 2H), 3.91 (s, 1H), 2.92 (d, J = 16.0 Hz, 1H), 1.71(d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H). LCMS Method D; t_(R):3.35 min; m/z: 405 [M + H] Example 34

3-ethyl-16-fluoro-20-oxa-3,4,8,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,9,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.89 (s, 1H), 7.69 (s, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.45-7.40(m, 1H), 7.26 (t, J = 2.4 Hz, 2H), 7.09 (d, J= 1.2 Hz, 1H), 6.21 (s,2H), 5.63 (d, J = 1.8 Hz, 1H), 5.27 (s, 1H), 5.16 (d, J = 13.2 Hz, 1H),5.05 (d, J = 14.7 Hz, 1H), 4.24 (d, J = 14.6 Hz, 1H), 4.08 (dd, J = 7.2,3.3 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). LCMS Method B; t_(R): 2.40 min;m/z: 391 [M + H] Example 35

3-ethyl-17-fluoro-20-methyl-21-oxa-3,4,11,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23-undecaen-23- amine 1H NMR(400 MHz, DMSO) δ 8.57 (d, J = 5.2 Hz, 1H), 8.37 (s, 1H), 7.79 (s, 1H),7.73 (dd, J = 10.4, 2.2 Hz, 1H), 7.47 (t, J = 4.1 Hz, 2H), 7.23-7.17 (m,2H), 6.16 (s, 2H), 5.98 (d, J = 1.7 Hz, 1H), 5.13 (q, J = 6.7 Hz, 1H),4.12- 4.03 (m, 2H), 3.77 (d, J = 15.7 Hz, 1H), 3.06 (d, J = 15.6 Hz,1H), 1.80 (d, J = 6.3 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H). LCMS Method C;t_(R): 0.96 min; m/z: 416 [M + H] Example 36

3-ethyl-17-fluoro-20-methyl-21-oxa-3,4,10,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23-undecaen-23- amine 1H NMR(400 MHz, DMSO) δ 8.71 (s, 1H), 8.47 (d, J = 4.9 Hz, 1H), 7.83 (s, 1H),7.72 (d, J = 9.8 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.26-7.14 (m, 3H),6.15 (s, 2H), 6.06 (d, J = 1.5 Hz, 1H), 5.21-5.11 (m, 1H), 4.07 (m, 2H),3.83 (d, J = 15.7 Hz, 1H), 3.05 (d, J = 15.6 Hz, 1H), 1.79 (d, J = 6.2Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H). LCMS Method C; t_(R): 0.80 min; m/z:416 [M + H] Example 37

3-cyclobutyl-16-fluoro-19-methyl-20-oxa-3,4,8,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,9,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.92 (s, 1H), 7.75 (dd, J = 10.3, 2.8 Hz, 1H), 7.38 (dd, J =8.5, 5.7 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.26 (d, J = 1.3 Hz, 1H),7.21 (td, J = 8.4, 2.8 Hz, 1H), 7.09 (d, J = 1.2 Hz, 1H), 6.21 (s, 2H),5.63 (d, J = 1.8 Hz, 1H), 5.57-5.48 (m, 1H), 5.02 (d, J = 14.8 Hz, 1H),4.78 (p, J = 8.3 Hz, 1H), 4.18 (d, J = 14.7 Hz, 1H), 2.65 (p, J = 10.2Hz, 1H), 2.48-2.36 (m, 2H), 2.16-2.03 (m, 1H), 1.80-1.65(m, 5H). LCMSMethod D; t_(R): 2.67 min; m/z: 431 [M + H] Example 38

3-ethyl-16-fluoro-19-methyl-20-oxa-3,4,10,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.86-7.81 (m, 2H), 7.65 (s, 1H), 7.50 (s, 1H), 7.41-7.28 (m,2H), 6.81 (s, 1H), 6.20 (br s, 3H), 5.18-5.09 (m, 1H), 4.14-4.01 (m,2H), 3.77 (d, J = 16.7 Hz, 1H), 2.73 (d, J = 16.2 Hz, 1H), 1.78 (d, J =6.3 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H). LCMS Method D; t_(R): 1.94 min;m/z: 405 [M + H] Example 39

16-fluoro-3-(2-fluoroethyl)-19-methyl-20-oxa- 3,4,8,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,9,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.97 (s, 1H), 7.79-7.72 (m, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.38(dd, J = 8.6, 5.7 Hz, 1H), 7.28 (d, J = 1.2 Hz, 1H), 7.24-7.19 (m, 1H),7.11 (d, J = 1.2 Hz, 1H), 6.22 (s, 2H), 5.66 (s, 1H), 5.51 (s, 1H), 5.04(d, J = 14.8 Hz, 1H),4.81 (ddd, J = 31.2, 18.1, 4.4 Hz, 2H), 4.40-4.35(m, 2H), 4.22 (s, 1H), 1.75 (d, J = 6.3 Hz, 3H). LCMS Method C; t_(R):1.16 min; m/z: 423 [M + H] Example 40

3-(2,2-difluoroethyl)-16-fluoro-19-methyl-20-oxa- 3,4,8,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,9,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 8.01 (s, 1H), 7.76 (dd, J = 10.3, 2.8 Hz, 1H), 7.50 (d, J =1.9 Hz, 1H), 7.38 (dd, J = 8.6, 5.7 Hz, 1H), 7.28 (d, J = 1.3 Hz, 1H),7.22 (td, J = 8.5, 2.8 Hz, 1H), 7.11 (d, J = 1.3 Hz, 1H), 6.52-6.20 (m,3H), 5.64 (d, J = 2.0 Hz, 1H), 5.58-5.47 (m, 1H), 5.04 (d, J = 14.8 Hz,1H), 4.51 (qd, J = 14.8, 4.0 Hz, 2H), 4.21 (d, J = 14.7 Hz, 1H), 1.74(d, J = 6.2 Hz, 3H). LCMS Method D; t_(R): 0.60 min; m/z: 441 [M + H]Example 41

3-ethyl-16-fluoro-20-oxa-3,4,11,12,23- pentaazapentacyclo[19.3.1.0²,⁶0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.77 (dd, J = 9.4, 2.9 Hz, 1H), 7.66 (d, J = 2.3 Hz, 2H),7.50 (d, J = 1.7 Hz, 1H), 7.40 (dd, J = 8.8, 5.2 Hz, 1H), 7.31 (td, J =8.4, 3.0 Hz, 1H), 6.22 (d, J = 1.8 Hz, 1H), 6.19 (s, 2H), 6.00 (d, J =1.8 Hz, 1H), 5.14 (d, J = 13.5 Hz, 1H), 4.90 (d, J = 13.6 Hz, 1H), 4.07(qd, J = 7.0, 3.7 Hz, 2H), 3.91 (d, J = 16.2 Hz, 1H), 2.95 (d, J = 16.1Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H). LCMS Method D; t_(R): 2.82 min; m/z:391 [M + H] Example 42

3-ethyl-17-fluoro-20-methyl-21-oxa-3,4,10,12,24-pentaazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23-undecaen-23- amine 1H NMR(400 MHz, DMSO) δ 9.10 (s, 1H), 8.92 (s, 1H), 7.85 (s, 1H), 7.76 (dd, J= 10.4, 2.6 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.29-7.15 (m, 2H), 6.15(s, 2H), 6.07 (d, J = 1.7 Hz, 1H), 5.37-5.23 (m, 1H), 4.13-3.98 (m, 2H),3.93 (d, J = 15.7 Hz, 1H), 3.04 (d, J = 15.6 Hz, 1H), 1.75 (d, J = 6.2Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H). LCMS Method C; t_(R): 0.97 min; m/z:417 [M + H] Example 43

(19R)-3-ethyl-16-fluoro-19-methyl-20-oxa- 3,4,10,11,12,23-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,MeOD) δ 7.79-7.75 (m, 2H), 7.72 (s, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.39(dd, J = 8.8, 5.0 Hz, 1H), 7.28 (ddd, J = 8.8, 7.7, 2.9 Hz, 1H), 6.09(d, J = 1.7 Hz, 1H), 5.20 (dd, J = 6.4, 1.9 Hz, 1H), 4.59 (s, 2H), 4.16(ddt, J = 21.3, 14.1, 7.1 Hz, 2H), 4.03 (d, J = 17.2 Hz, 1H), 3.16 (d, J= 16.4 Hz, 1H), 1.83 (d, J = 6.3 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H). LCMSMethod C; t_(R): 0.87 min; m/z: 406 [M + H] Example 44

3-(difluoromethyl)-16-fluoro-19-methyl-20-oxa- 3,4,8,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,9,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 8.29 (s, 1H), 7.75 (dd, J = 10.3, 2.7 Hz, 1H), 7.68-7.66 (t,1H), 7.42 (s, 1H), 7.39 (dd, J = 8.6, 5.8 Hz, 1H), 7.31 (d, J = 1.3 Hz,1H), 7.23 (td, J = 8.4, 2.7 Hz, 1H), 7.13 (d, J = 1.3 Hz, 1H), 6.38 (s,2H), 5.67 (s, 1H), 5.57-5.49 (m, 1H), 5.10 (d, J = 14.8 Hz, 1H), 4.23(d, J = 14.7 Hz, 1H), 1.75 (d, J = 6.3 Hz, 3H). LCMS Method C; t_(R):2.56 min; m/z: 427 [M + H] Example 45

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa- 3,4,8,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,9,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.84 (s, 1H), 7.74 (dd, J = 10.4, 2.8 Hz, 1H), 7.47 (d, J =1.8 Hz, 1H), 7.34 (dd, J = 8.6, 5.8 Hz, 1H), 7.22-7.17 (m, 1H), 6.96 (d,J = 1.2 Hz, 1H), 6.19 (s, 2H), 5.73 (s, 1H), 5.56 (d, J = 7.3 Hz, 1H),4.93 (d, J = 14.6 Hz, 1H), 4.13-4.04 (m, 3H), 2.14 (d, J = 1.0 Hz, 3H),1.74 (d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H). LCMS Method D;t_(R): 2.04 min; m/z: 419 [M + H] Example 46

(19R)-3-ethyl-9,16-difluoro-19-methyl-20-oxa- 3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.85 (dd, J = 9.8, 2.9 Hz, 1H), 7.79 (d, J = 3.9 Hz, 1H),7.58 (d, J = 1.4 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.35 (dd, J = 8.7,5.2 Hz, 1H), 7.27 (td, J = 8.4, 2.9 Hz, 1H), 6.20 (s, 2H), 6.17 (d, J =1.9 Hz, 1H), 5.31 (q, J = 6.0 Hz, 1H), 409-3.99 (m, 3H), 2.96 (d, J =16.3 Hz, 1H), 1.72 (d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H). LCMSMethod G; t_(R): 3.35 min; m/z: 423 [M + H] Example 47

(19R)-22-amino-3-ethyl-16-fluoro-19-methyl-20-oxa- 3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaene-9- carbonitrile 1H NMR (400MHz, DMSO) δ 8.30 (s, 1H), 7.90 (dd, J = 9.8, 2.9 Hz, 1H), 7.67 (s, 1H),7.48 (d, J = 1.8 Hz, 1H), 7.44 (dd, J = 8.8, 5.1 Hz, 1H), 7.34-7.29 (m,1H), 6.23 (s, 2H), 6.11 (s, 1H), 5.29 (d, J = 5.4 Hz, 1H), 4.21 (d, J =16.5 Hz, 1H), 4.12-4.02 (m, 2H), 3.12 (d, J = 16.2 Hz, 1H), 1.71 (d, J =6.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H). LCMS Method F; t_(R): 0.96 min;m/z: 430 [M + H] Example 48

3-ethyl-9,16-difluoro-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.79 (dd, J = 9.9, 3.3 Hz, 2H), 7.59 (d, J = 1.5 Hz, 1H),7.51 (d, J = 1.9 Hz, 1H), 7.39 (dd, J = 8.9, 5.3 Hz, 1H), 7.32 (td, J =8.2, 2.9 Hz, 1H), 6.20 (s, 2H), 6.16 (d, J = 1.7 Hz, 1H), 5.16 (d, J =13.5 Hz, 1H), 5.07 (d, J = 13.6 Hz, 1H), 4.13-4.00 (m, 3H), 3.00 (d, J =16.3 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H). LCMS Method G; t_(R): 2.93 min;m/z: 409 [M + H] Example 49

3-ethyl-16-fluoro-10-methyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-dccacn-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.65 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 10.7 Hz, 2H), 7.44 (d,J = 1.7 Hz, 1H), 7.18 (d, J = 7.2 Hz, 2H), 6.29 (s, 1H), 6.09 (s, 2H),5.08 (dd, J = 28.5, 13.6 Hz, 2H), 4.02 (d, J = 7.3 Hz, 2H), 3.84 (s,3H), 3.63-3.61 (m, 1H), 2.72 (s, 1H), 1.28 (t, J = 7.2 Hz, 3H) LCMSMethod F; t_(R): 0.81 min; m/z: 405 [M + H] Example 50

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa- 4,6,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,4,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (300 MHz,DMSO-d6) δ 7.95 (s, 1H), 7.86 (s, 1H), 7.73 (dd, J = 10.4, 2.5 Hz, 1H),7.30 (d, J = 1.7 Hz, 1H), 7.19-7.08 (m, 2H), 6.28 (s, 1H), 5.98 (s, 2H),5.45- 5.33 (m, 1H), 5.19 (d, J = 15.8 Hz, 1H), 3.90 (s, 3H), 3.89 (d, J= 15.7 Hz, 1H), 2.46-2.31 (m, 2H), 1.72 (d, J = 6.1 Hz, 3H), 1.09 (t, J= 7.6 Hz, 3H). LCMS Method I; t_(R): 0.99 min; m/z: 419 [M + H] Example51

(19R)-22-amino-3-ethyl-16-fluoro-19-methyl-20-oxa- 3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaene-10- carbonitrile 1H NMR(400 MHz, DMSO) δ 7.52 (s, 1H), 7.46 (d, J = 1.7 Hz, 1H), 7.14 (t, J =8.7 Hz, 2H), 6.99-6.92 (m, 2H), 6.65 (s, 1H), 6.01 (q, J = 6.4 Hz, 1H),5.89 (s, 2H), 4.45 (d, J = 16.8 Hz, 1H), 4.25-4.11 (m, 2H), 3.80 (d, J =17.0 Hz, 1H), 1.99 (d, J = 6.6 Hz, 3H), 1.31 (t, J = 6.7 Hz, 3H). LCMSMethod H; t_(R): 0.67 min; m/z: 430 [M + H] Example 52

(19R)-3-ethyl-16-fluoro-19-methyl-10-(trifluoromethyl)-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.91 (dd, J = 9.8, 2.9 Hz, 1H), 7.71 (s, 1H), 7.55-7.49 (m, 2H),7.33 (td, J = 8.3, 2.9 Hz, 1H), 6.73 (s, 1H), 6.25 (s, 2H), 6.04 (d, J =1.5 Hz, 1H), 5.08 (d, J = 4.9 Hz, 1H), 4.13-4.02 (m, 2H), 3.96 (d, J =16.5 Hz, 1H), 2.93 (d, J = 16.2 Hz, 1H), 1.71 (d, J = 6.2 Hz, 3H), 1.30(t, J = 7.2 Hz, 3H). LCMS Method H; t_(R): 1.29 min; m/z: 473 [M + H]Example 53

(19R)-3-(cyclopropylmethyl)-16-fluoro-5,10,19-trimcthyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.69 (d, J = 10.3 Hz, 1H), 7.62 (s, 1H), 7.42 (d, J = 1.8 Hz,1H), 7.17-7.11 (m, 2H), 6.29 (d, J = 1.6 Hz, 1H), 6.15 (s, 2H), 5.31 (m,1H), 3.92- 3.87 (m, 1H), 3.86 (s, 3H), 3.73 (dd, J = 14.4, 7.4 Hz, 1H),3.48 (d, J = 15.8 Hz, 1H), 2.66 (d, J = 15.6 Hz, 1H), 2.33 (s, 3H), 1.70(d, J = 6.3 Hz, 3H), 1.08 (m, 1H), 0.47- 0.31 (m, 2H), 0.22 (td, J =9.1, 4.8 Hz, 1H), 0.05 (td, J = 9.3, 5.1 Hz, 1H). LCMS Method H; t_(R):0.88 min; m/z: 459 [M + H] Example 54

(19R)-9-chloro-3-(cyclopropylmethyl)-16-fluoro-5,10,19-trimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,MeOD) δ 7.55 (dd, J = 10.0, 2.6 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H), 7.29(dd, J = 8.6, 5.7 Hz, 1H), 7.15 (td, J = 8.4, 2.7 Hz, 1H), 6.88 (d, J =1.6 Hz, 1H), 5.79-5.71 (m, 1H), 4.00 (dd, J = 14.7, 6.3 Hz, 1H),3.95-3.86 (m, 4H), 3.71 (d, J = 16.3 Hz, 1H), 3.17-3.10 (m, 1H), 2.46(s, 3H), 1.89 (d, J = 6.4 Hz, 3H), 1.13-1.02 (m, 1H), 0.51-0.38 (m, 2H),0.26 (dt, J = 8.7, 5.0 Hz, 1H), 0.11-0.03 (m, 1H). LCMS Method F; t_(R):1.14 min; m/z: 493 [M + H] Example 55

3-ethyl-16-fluoro-5,10-dimethyl-20-oxa-4,5,11,12,23-pentaazapentacyclo[19.3.1.0²,^(6.)0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,10,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.74 (dd, J = 9.4, 2.8 Hz, 1H), 7.41-7.35 (m, 2H), 7.35-7.28 (m,1H), 6.13 (s, 1H), 6.01 (d, J = 1.5 Hz, 1H), 5.80 (s, 2H), 5.13 (d, J =13.5 Hz, 1H), 4.92 (d, J = 14.1 Hz, 1H), 4.19 (d, J = 16.7 Hz, 1H), 3.96(s, 3H), 3.13 (d, J = 16.6 Hz, 1H), 2.56 (dd, J = 15.1, 7.6 Hz, 2H),2.22 (s, 3H), 1.12 (t, J = 7.5 Hz, 3H). LCMS Method F; t_(R): 0.45 min;m/z: 419 [M + H] Example 56

(19R)-3-(cyclopropylmethyl)-16-fluoro-5,10,19-trimethyl-20-oxa-3,4,8,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,9,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.57 (s, 1H), 7.48 (s, 1H), 7.37 (d, J = 1.5 Hz, 1H), 7.15 (d, J= 9.9 Hz, 1H), 7.10- 7.05 (m, 2H), 6.14 (s, 2H), 5.83 (d, J = 6.0 Hz,1H), 4.84 (d, J = 14.8 Hz, 1H), 4.51 (d, J = 14.8 Hz, 1H), 3.42 (dd, J =14.3, 6.1 Hz, 1H), 2.92 (dd, J = 13.9, 7.9 Hz, 1H), 2.09 (s, 3H), 2.02(s, 3H), 1.23 (d, J = 6.1 Hz, 3H), 0.38 (s, 1H), 0.06-0.01 (m, 2H),−0.22-−0.33 (m, 2H). LCMS Method K; t_(R): 1.13 min; m/z: 459 [M + H]Example 57

(19R)-5-(benzyloxy)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine LCMS Method M;t_(R): 3.35 min; m/z: 525 [M + H]

Example 58 (Method D)

-   -   Name:        (19R)-22-amino-16-fluoro-19-methyl-20-oxa-4,6,11,12,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-1(24),2,4,8,10,13,15,17,21(25),22-decaene-3-carbonitrile    -   NMR: 1H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 7.89-7.76 (m, 2H),        7.60 (d, J=1.7 Hz, 1H), 7.41 (dd, J=8.7, 5.2 Hz, 1H), 7.35-7.26        (m, 1H), 6.58 (s, 1H), 6.46 (br s, 2H), 6.02 (s, 1H), 5.63 (d,        J=16.7 Hz, 1H), 5.28-5.17 (m, 1H), 4.27 (d, J=16.7 Hz, 1H), 1.74        (d, J=6.1 Hz, 3H).

LCMS: Method C; t_(R): 1.04 min; m/z: 402 [M+H]

To a solution of1-{[1-(2-{1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl}-4-fluorophenyl)-1H-pyrazol-5-yl]methyl}-1H-imidazole-4-carbonitrile(140 mg, 0.27 mmol) in EtOH (6 mL) and H₂O (2 mL) was added ammoniumchloride (188 mg, 3.51 mmol) and iron powder (153 mg, 3.51 mmol). Thereaction was stirred at 80° C. for 1 h. The mixture was filtered, andthe filtrate was concentrated in vacuo. The residue was partitionedbetween ice water, and EtOAc. The organic layer was separated, washedwith brine, dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by flash chromatography (silica gel,0→20% MeOH in DCM) to give1-{[1-(2-{1-[(2-amino-5-bromopyridin-3-yl)oxy]ethyl}-4-fluorophenyl)-1H-pyrazol-5-yl]methyl}-1H-imidazole-4-carbonitrile(81 mg, yield: 61%) as a yellow solid. LC/MS (ESI) m/z: 482 [M+H]⁺.

To a solution of1-{[1-(2-{1-[(2-amino-5-bromopyridin-3-yl)oxy]ethyl}-4-fluorophenyl)-1H-pyrazol-5-yl]methyl}-1H-imidazole-4-carbonitrile(100 mg, 0.21 mmol) in 2-methyl-2-butanol (5 mL) was added potassiumacetate (122 mg, 1.24 mmol), Pd(OAc)₂ (19 mg, 0.080 mmol) and cataCXiumA (31 mg, 0.080 mmol). The mixture was thrice degassed under N₂, and thereaction was stirred at 120° C. for 16 h. The mixture was diluted withwater and extracted with EtOAc. The organic layer was washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by prep-TLC (10% MeOH in DCM) followed by chiralSFC (ChiralPak AS-H 4.6*250 mm, 4→40% MeOH+0.05% DEA in CO₂ over 8.5min) to give the target product (eutomer: t_(R) 5.25 min, 5.4 mg;distomer: t_(R) 5.85 min, 7.6 mg) as a white solid. LC/MS (ESI) m/z: 402[M+H]⁺.

The following compounds were prepared in a similar manner:

Example  59

23-amino-17-fluoro-4,20-dimethyl-21-oxa-4,5,10,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2,5,8(13),9,11,14,16,18,22(26),23-undecaene- 3-carbonitrile 1H NMR(400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.54 (d, J = 4.9 Hz, 1H), 7.67 (dd, J= 10.2, 2.7 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.36-7.17 (m, 3H), 6.14(s, 2H), 6.06 (s, 1H), 5.11-5.02 (m, 1H), 4.13 (d, J = 15.6 Hz, 1H),4.07 (s, 3H), 3.3 (d, 1H), 1.80 (d, J = 6.2 Hz, 3H) LCMS Method A;t_(R): 1.14 min; m/z: 427 [M + H] Example  60

22-amino-16-fluoro-11,19-dimethyl-20-oxa- 5,6,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,4,8(12),9,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, DMSO) δ 8.17 (s, 1H), 7.84 (dd, J = 10.3, 2.6 Hz, 1H), 7.64 (d, J =1.6 Hz, 1H), 7.57 (s, 1H), 7.30 (td, J = 8.3, 2.6 Hz, 1H), 7.22 (dd, J =8.5, 5.9 Hz, 1H), 6.64 (s, 1H), 6.51 (s, 2H), 5.32 (d, J = 15.9 Hz, 1H),5.18-5.05 (m, 1H), 4.22 (d, J = 15.8 Hz, 1H), 3.62 (s, 3H), 1.81 (d, J =6.1 Hz, 3H). LCMS Method C; t_(R): 1.17 min; m/z: 416 [M + H] Example 61

(19R)-22-amino-16-fluoro-10,19-dimethyl-20-oxa- 4,6,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,4,8,10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, DMSO) δ 8.16 (s, 1H), 7.86 (d, J = 10.0 Hz, 1H), 7.47 (d, J = 1.7Hz, 1H), 7.35 (d, J = 6.8 Hz, 2H), 6.24 (s, 1H), 5.96 (s, 3H), 5.45 (d,J = 14.7 Hz, 1H), 5.00 (s, 1H), 4.62 (d, J = 14.5 Hz, 1H), 2.07 (s, 3H),1.65 (d, J = 6.4 Hz, 3H). LCMS Method C; t_(R): 0.91 min; m/z: 416 [M +H] Example  62

(19R)-22-amino-16-fluoro-19-methyl-20-oxa- 5,6,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,4,8,10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, DMSO) δ 8.22 (s, 1H), 7.86- 7.81 (m, 2H), 7.66-7.63 (m, 1H),7.50-7.44 (m, 1H), 7.36-7.27 (m, 1H), 6.58-6.55 (m, 2H), 6.46-6.44 (m,1H), 6.08-6.06 (m, 1H), 5.70-5.64 (m, 1H), 5.31- 5.14 (m, 1H), 4.55-4.49(m, 1H), 1.75 (s, 3H). LCMS Method D; t_(R): 1.26 min; m/z: 402 [M + H]Example  63

(20R)-23-amino-10,17-difluoro-20-methyl-21-oxa- 4,6,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2,4,8,10,12,14(19),15,17,22(26),23-undecaene- 3-carbonitrile 1HNMR (400 MHz, DMSO) δ 8.79 (d, J = 2.7 Hz, 1H), 8.53 (s, 1H), 7.96 (dd,J = 9.5, 2.6 Hz, 1H), 7.78 (dd, J = 10.3, 2.4 Hz, 1H), 7.65 (d, J = 1.9Hz, 1H), 7.31-7.22 (m, 2H), 6.50 (s, 2H), 6.21 (d, J = 1.6 Hz, 1H), 5.61(d, J = 16.4 Hz, 1H), 5.25 (d, J = 6.0 Hz, 1H), 4.37 (d, J = 15.7 Hz,1H), 1.81 (d, J = 6.2 Hz, 3H). LCMS Method C; t_(R): 1.20 min; m/z: 431[M + H] Example  64

(19R)-22-amino-16-fluoro-19-methyl-20-oxa-9-thia- 4,6,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,4,8(12),10,13(18),14,16,21(25),22-decaene- 3-carbonitrile 1H NMR(400 MHz, DMSO) δ 9.26 (s, 1H), 8.37 (s, 1H), 7.73 (d, J = 9.8 Hz, 1H),7.55 (s, 1H), 7.22 (s, 2H), 6.41 (s, 2H), 6.26 (s, 1H), 5.73 (d, J =16.0 Hz, 1H), 5.14 (s, 1H), 4.49 (d, J = 16.3 Hz, 1H), 1.73 (d, J = 5.4Hz, 3H). LCMS Method C; t_(R): 1.06 min; m/z: 419 [M + H] Example  65

(19R)-22-amino-16-fluoro-10,19-dimethyl-20-oxa-9- thia-4,6,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,4,8(12),10,13(18),14,16,21(25),22-decaene- 3-carbonitrile 1H NMR(400 MHz, DMSO) δ 8.34 (s, 1H), 7.73 (d, J = 9.6 Hz, 1H), 7.55 (d, J =1.7 Hz, 1H), 7.20 (d, J = 7.2 Hz, 2H), 6.40 (d, J = 4.6 Hz, 3H), 5.67(d, J = 16.1 Hz, 1H), 5.23 (d, J = 5.8 Hz, 1H), 4.42 (d, J = 16.1 Hz,1H), 2.70 (s, 3H), 1.73 (d, J = 6.2 Hz, 3H). LCMS Method C; t_(R): 0.95min; m/z: 433 [M + H] Example  66

22-amino-16-fluoro-11,19-dimethyl-4-{[2-(trimethylsilyl)ethoxy]methyl}-20-oxa-4,5,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,5,8(12),9,13,15,17,21(25),22-decaene-3- carbonitrile LCMS MethodC; t_(R): 1.56 min; m/z: 546 [M + H] Example  67

(19R)-22-amino-16-fluoro-10,19-dimethyl-20-oxa-9- thia-5,6,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,4,8(12),10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR(400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.66 (dd, J = 10.3, 2.6 Hz, 1H), 7.55(d, J = 1.9 Hz, 1H), 7.19-7.10 (m, 2H), 6.45-6.39 (m, 3H), 5.57 (d, J =16.1 Hz, 1H), 5.15 (d, J = 6.4 Hz, 1H), 4.59 (d, J = 16.1 Hz, 1H), 2.62(s, 3H), 1.67 (d, J = 6.2 Hz, 3H). LCMS Method B; t_(R): 2.53 min; m/z:433 [M + H] Example  68

(19R)-3-(difluoromethyl)-16-fluoro-10,19-dimethyl-20-oxa-9-thia-5,6,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa- 1(24),2,4,8(12),10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz, DMSO) δ7.86 (s, 1H), 7.78 (dd, J = 10.3, 2.6 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H),7.26- 7.15 (m, 2H), 6.89 (t, J = 55 Hz, 1H), 6.42 (d, J = 1.7 Hz, 1H),6.33 (s, 2H), 5.57 (d, J = 16.0 Hz, 1H), 5.30- 5.20 (m, 1H), 4.60 (d, J= 16.0 Hz, 1H), 2.68 (s, 3H), 1.73 (d, J = 6.2 Hz, 3H). LCMS Method F;t_(R): 1.24 min; m/z: 458 [M + H] Example  69

3-ethyl-16-fluoro-10-methyl-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-dccacn-22- amine 1H NMR (400 MHz,DMSO-d6) δ 7.74 (dd, J = 9.4, 2.9 Hz, 1H),7.64 (s, 1H), 7.50 (d, J = 1.8Hz, 1H), 7.37- 7.26 (m, 2H), 6.18 (s, 2H), 6.10 (d, J = 1.9 Hz, 1H),6.02 (s, 1H), 5.13 (d, J = 13.5 Hz, 1H), 4.98 (d, J =13.2 Hz, 1H), 4.07(qd, J = 7.0, 2.9 Hz, 2H), 3.86 (d, J = 16.2 Hz, 1H), 2.89 (d, J = 16.0Hz, 1H), 2.19 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). LCMS Method H; t_(R):0.89 min; m/z: 405 [M + H] Example  70

(20R)-3-ethyl-10,17-difluoro-20-methyl-21-oxa- 3,4,5,12,24-pentaazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23- undecaen-23-amine 1H NMR(400 MHz, DMSO-d6) δ 8.59 (d, J = 2.8 Hz, 1H), 7.67 (ddd, J = 14.7, 9.9,2.8 Hz, 2H), 7.59 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 8.6, 5.8 Hz, 1H),7.22-7.16 (m, 1H), 6.29 (s, 2H), 6.00 (d, J = 1.9 Hz, 1H), 5.13 (d, J =4.2 Hz, 1H), 4.34 (qd, J = 7.0, 2.9 Hz, 2H), 4.20 (d, J = 15.6 Hz, 1H),3.25 (s, 1H), 1.72 (d, J = 6.2 Hz, 3H), 1.36 (t, J = 7.3 Hz, 3H). LCMSMethod F; t_(R): 0.90 min; m/z: 435 [M + H] Example  71

(19R)-3-ethyl-10,16-difluoro-19-methyl-20-oxa- 3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO-d6) δ 7.84 (dd, J = 9.8, 2.9 Hz, 1H), 7.65 (s, 1H), 7.50 (d, J =1.8 Hz, 1H), 7.42 (dd, J = 8.8, 5.2 Hz, 1H), 7.27 (td, J = 8.3, 3.0 Hz,1H), 6.26-6.16 (m, 3H), 6.03 (d, J = 5.4 Hz, 1H), 5.30 (q, J = 5.9 Hz,1H), 4.15-4.00 (m, 2H), 3.88 (d, J = 16.2 Hz, 1H), 2.85 (dd, J = 16.2,1.8 Hz, 1H), 1.70 (d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H). LCMSMethod F; t_(R): 1.09 min; m/z: 423 [M + H] Example  72

(19R)-3-(difluoromethyl)-16-fluoro-10,19-dimethyl-20-oxa-9-thia-3,4,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400MHz, DMSO) δ 7.97 (s, 1H), 7.72 (dd, J = 10.3, 2.6 Hz, 1H), 7.64 (t, J =56 Hz, 1H), 7.41 (d, J = 1.4 Hz, 1H), 7.23-7.13 (m, 2H), 6.34 (d, J =1.7 Hz, 1H), 6.32 (s, 2H), 5.23-5.16 (m, 1H), 4.02 (d, J = 15.7 Hz, 1H),3.18 (d, J = 15.6 Hz, 1H), 2.64 (s, 3H), 1.71 (d, J = 6.2 Hz, 3H). LCMSMethod F; t_(R): 1.19 min; m/z: 458 [M + H] Example  73

(19R)-5-chloro-3-ethyl-16-fluoro-10,19-dimethyl-20- oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.71 (dd, J = 10.4, 2.4 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 1.8Hz, 1H), 7.22- 7.09 (m, 2H), 6.32-6.15 (m, 3H), 5.36-5.24 (m, 1H),4.07-3.92 (m, 2H), 3.87 (s, 3H), 3.54 (d, J = 15.9 Hz, 1H), 2.70 (d, J =15.6 Hz, 1H), 1.71 (d, J = 6.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H). LCMSMethod H; t_(R): 1.06 min; m/z: 453 [M + H] Example  74

(19R)-10-chloro-3-ethyl-16-fluoro-19-methyl-20- oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.93 (dd, J = 9.8, 2.9 Hz, 1H), 7.72 (s, 1H), 7.56 (d, J = 1.8Hz, 1H), 7.49 (dd, J = 8.8, 5.2 Hz, 1H), 7.35 (td, J = 8.3, 3.0 Hz, 1H),6.42 (s, 1H), 6.31 (s, 2H), 6.19 (d, J = 1.7 Hz, 1H), 5.29 (d, J = 4.9Hz, 1H), 4.12 (tq, J = 14.3, 7.1 Hz, 2H), 3.95 (d, J = 16.5 Hz, 1H),2.92 (d, J = 16.1 Hz, 1H), 1.77 (d, J = 6.2 Hz, 3H), 1.35 (t, J = 7.2Hz, 3H). LCMS Method H; t_(R): 1.14 min; m/z: 439 [M + H] Example  75

10-chloro-3-ethyl-16-fluoro-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.80 (dd, J = 9.4, 2.9 Hz, 1H), 7.67 (s, 1H), 7.52 (d, J = 1.7Hz, 1H), 7.46 (dd, J = 8.8, 5.2 Hz, 1H), 7.34 (td, J = 8.4, 2.9 Hz, 1H),6.35 (s, 1H), 6.23 (s, 2H), 6.14 (d, J = 1.5 Hz, 1H), 5.08 (dd, J =80.5, 13.8 Hz, 2H), 4.15-3.99 (m, 2H), 3.92 (d, J = 16.3 Hz, 1H), 2.91(d, J = 16.1 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H). LCMS Method F; t_(R):1.03 min; m/z: 425 [M + H] Example  76

(19R)-5-chloro-3-ethyl-16-fluoro-10,19-dimethyl-20- oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO-d6) δ 7.81 (dd, J = 9.8, 3.0 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H),7.39 (dd, J = 8.7, 5.2 Hz, 1H), 7.25 (td, J = 8.3, 3.0 Hz, 1H), 6.31 (s,2H), 6.10 (d, J = 1.9 Hz, 1H), 6.06 (s, 1H), 5.22 (d, J = 6.6 Hz, 1H),4.06 (qd, J = 7.0, 3.4 Hz, 2H), 3.81 (d, J = 16.4 Hz, 1H), 2.86 (d, J =16.3 Hz, 1H), 2.22 (s, 3H), 1.72 (d, J = 6.2 Hz, 3H), 1.30 (t, J = 7.2Hz, 3H). LCMS Method J; t_(R): 2.70 min; m/z: 453 [M + H] Example  77

(19R)-3-ethyl-16-fluoro-19-methyl-9,20-dioxa- 3,4,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400MHz, DMSO-d6) δ 8.38 (s, 1H), 7.79 (dd, J = 10.4, 2.7 Hz, 1H), 7.61 (s,1H), 7.43 (d, J = 1.8 Hz, 1H), 7.20 (dd, J = 8.5, 6.0 Hz, 1H), 7.16 (td,J = 8.4, 2.6 Hz, 1H), 6.27 (d, J = 1.9 Hz, 1H), 6.13 (s, 2H), 5.33 (qd,J = 6.5, 5.8, 1.3 Hz, 1H), 4.06-3.94 (m, 2H), 3.89 (d, J = 15.9 Hz, 1H),3.17 (d, J = 15.9 Hz, 1H), 1.72 (d, J = 6.2 Hz, 3H), 1.26 (t, J = 7.2Hz, 3H). LCMS Method G; t_(R): 2.34 min; m/z: 406 [M + H] Example  78

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-9- thia-3,4,5,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400MHz, DMSO) δ 7.70 (dd, J = 10.3, 2.7 Hz, 1H), 7.57 (d, J = 1.7 Hz, 1H),7.27 (dd, J = 8.5, 5.9 Hz, 1H), 7.18 (td, J = 8.4, 2.7 Hz, 1H), 6.27 (s,3H), 5.19-5.11 (m, 1H), 4.37-4.26 (m, 2H), 4.23 (d, J = 15.7 Hz, 1H),3.40 (t, J = 10.7 Hz, 1H), 2.64 (s, 3H), 1.71 (d, J = 6.2 Hz, 3H), 1.33(t, J = 7.3 Hz, 3H). LCMS Method F; t_(R): 0.94 min; m/z: 437 [M + H]Example  79

(19R)-3-(2,2-difluoroethyl)-16-fluoro-5,10,19-trimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.70 (d, J = 10.4 Hz, 1H), 7.62 (s, 1H), 7.42 (d, J = 1.6 Hz,1H), 7.15 (d, J = 7.1 Hz, 2H), 6.46 6.32 6.18 (m, 1H), 6.27 (s, 1H),6.14 (s, 2H), 5.36-5.23 (m, 1H), 4.44-4.24 (m, 2H), 3.86 (s, 3H), 3.51(d, J = 15.9 Hz, 1H), 2.67 (d, J = 15.7 Hz, 1H), 2.35 (s, 3H), 1.70 (d,J = 6.2 Hz, 3H). LCMS Method F; t_(R): 0.91 min; m/z: 469 [M + H]Example  80

(19R)-10-bromo-3-ethyl-16-fluoro-19-methyl-20- oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.85 (dd, J = 9.8, 2.9 Hz, 1H), 7.67 (s, 1H), 7.50 (d, J = 1.7Hz, 1H), 7.40 (dd, J = 8.7, 5.2 Hz, 1H), 7.28 (td, J = 8.4, 3.0 Hz, 1H),6.40 (s, 1H), 6.22 (s, 2H), 6.11 (d, J = 1.3 Hz, 1H), 5.21 (q, J = 6.4Hz, 1H), 4.14-3.98 (m, 2H), 3.90 (d, J = 16.4 Hz, 1H), 2.87 (d, J = 16.1Hz, 1H), 1.72 (d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H). LCMS MethodF; t_(R): 1.11 min; m/z: 483 [M + H] Example  81

(19R)-3-ethyl-16-fluoro-5,10,19-trimethyl-20-oxa- 3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.69 (d, J = 10.3 Hz, 1H), 7.59 (s, 1H), 7.39 (s, 1H), 7.15 (d,J = 6.1 Hz, 2H), 6.28 (s, 1H), 6.07 (s, 2H), 5.29 (d, J = 4.7 Hz, 1H),3.97-3.89 (m, 2H), 3.85 (s, 3H), 3.48 (d, J = 15.7 Hz, 1H), 2.65 (d, J =15.6 Hz, 1H), 2.32 (s, 3H), 1.70 (d, J = 6.2 Hz, 3H), 1.23 (d, J = 7.1Hz, 3H). LCMS Method H; t_(R): 0.91 min; m/z: 433 [M + H] Example  82

(19R)-22-amino-16-fluoro-5,10,19-trimethyl-20-oxa- 9-thia-4,5,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8(12),10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR(400 MHz, DMSO) δ 7.68 (dd, J = 10.2, 1.9 Hz, 1H), 7.52 (d, J = 1.8 Hz,1H), 7.29-7.19 (m, 2H), 6.30 (d, J = 1.7 Hz, 1H), 6.10 (s, 2H),5.17-5.04 (m, 1H), 4.44 (d, J = 16.5 Hz, 1H), 4.11 (s, 3H), 3.49 (d, J =9.2 Hz, 1H), 2.69 (s, 3H), 1.72 (d, J = 6.2 Hz, 3H). LCMS Method F;t_(R): 0.93 min; m/z: 447 [M + H] Example  83

(19R)-5-chloro-3-(2,2-difluoroethyl)-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1,0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO-d6) δ 7.70 (dd, J = 10.4, 2.6 Hz, 1H), 7.60 (s, 1H),7.49 (d, J =1.8 Hz, 1H), 7.20- 7.12 (m, 2H), 6.50-6.19 (m, 4H), 5.31 (dd, J = 6.4,2.1 Hz, 1H), 4.52-4.37 (m, 2H), 3.87 (s, 3H), 3.56 (d, J = 15.7 Hz, 1H),2.71 (d, J = 15.6 Hz, 1H), 1.71 (d, J = 6.2 Hz, 3H). LCMS Method F;t_(R): 0.99 min; m/z: 489 [M + H] Example  84

(19R)-3-(2,2-difluoroethyl)-16-fluoro-19-methyl-10-(trifluoromethyl)-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,CDCl3) δ 7.73 (s, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.39 (dd, J = 9.0, 2.8Hz, 1H), 7.20- 7.05 (m, 2H), 6.53 (s, 1H), 6.24 (tt, J = 4, 56 Hz, 1H),6.19 (d, J = 4 Hz, 1H), 5.23-5.11 (m, 1H), 4.95 (br s, 2H), 4.54-4.38(m, 2H), 3.83 (d, J = 16.3 Hz, 1H), 3.22 (d, J = 16.2 Hz, 1H), 1.81 (d,J = 6.3 Hz, 3H). LCMS Method F; t_(R): 1.16 min; m/z: 509 [M + H]Example  85

(19R)-3-(2,2-difluoroethyl)-16-fluoro-10,19-dimethyl-5,20-dioxa-4,10,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,MeOD) δ 7.73 (s, 1H), 7.55 (dd, J = 9.9, 2.7 Hz, 1H), 7.41 (d, J = 1.6Hz, 1H), 7.29 (dd, J = 8.6, 5.7 Hz, 1H), 7.18 (td, J = 8.4, 2.7 Hz, 1H),6.70 (d, J = 1.6 Hz, 1H), 6.18 (tt, J = 4, 52 Hz, 1H), 5.61- 5.52 (m,1H), 4.16 (d, J = 15.9 Hz, 1H), 3.95 (s, 3H), 3.44 (d, J = 15.9 Hz, 1H),3.35 (d, J = 4.4 Hz, 1H), 3.26 (d, J = 4.4 Hz, 1H), 1.88 (d, J = 6.3 Hz,3H). LCMS Method F; t_(R): 0.96 min; m/z: 456 [M + H] Example  86

(19R)-10-(difluoromethyl)-3-ethyl-16-fluoro-19-methyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.97 (t, J = 56 Hz, 1H), 7.88 (s, 2H), 7.72 (d, J = 9.7 Hz, 1H),7.39 (d, J = 1.8 Hz, 1H), 7.17-7.10 (m, 2H), 6.26 (d, J = 1.6 Hz, 1H),6.13 (s, 2H), 5.34 (d, J = 4.6 Hz, 1H), 4.14 (d, J = 16.2 Hz, 1H), 4.01(dt, J = 10.4, 7.0 Hz, 2H), 3.41 (s, 1H), 1.82 (d, J = 6.3 Hz, 3H), 1.23(t, J = 7.1 Hz, 3H). LCMS Method F; t_(R): 1.05 min; m/z: 455 [M + H]Example  87

(19R)-3-ethyl-16-fluoro-9,10,19-trimethyl-20-oxa- 3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.69-7.62 (m, 2H), 7.37 (t, J = 5.4 Hz, 1H), 7.14-7.02 (m, 2H),6.39 (d, J = 1.5 Hz, 1H), 6.04 (s, 2H), 5.45 (dd, J = 8.6, 4.0 Hz, 1H),3.99 (q, J = 7.2 Hz, 2H), 3.74 (s, 3H), 3.62 (d, J = 15.6 Hz, 1H), 2.92(d, J = 15.5 Hz, 1H), 2.25 (s, 3H), 1.72 (d, J = 6.2 Hz, 3H), 1.26 (t, J= 7.2 Hz, 3H). LCMS Method F; t_(R): 0.89 min; m/z: 433 [M + H] Example 88

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-4- thia-5,10,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,5,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz, DMSO)δ 7.79-7.70 (m, 1H), 7.51 (s, 1H), 7.33 (s, 1H), 7.15 (d, J = 6.1 Hz,2H), 6.25 (s, 1H), 5.97 (s, 2H), 5.36 (d, J = 5.1 Hz, 1H), 3.89-3.81 (m,4H), 3.00 (d, J = 14.6 Hz, 1H), 2.87 (dd, J = 15.6, 7.6 Hz, 1H), 2.76(dd, J = 15.6, 7.6 Hz, 1H), 1.71 (d, J = 6.2 Hz, 3H), 1.18 (t, J = 7.5Hz, 3H). LCMS Method F; t_(R): 0.78 min; m/z: 436 [M + H] Example  89

3-ethyl-16-fluoro-10-methyl-20-oxa-9-thia- 3,4,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400MHz, CDCl3) δ 7.58 (s, 1H), 7.54 (s, 1H), 7.35 (dd, J = 9.3, 2.4 Hz,1H), 7.15 (dd, J = 8.4, 5.7 Hz, 1H), 7.07-6.98 (m, 1H), 6.56 (s, 1H),5.21 (d, J = 13.2 Hz, 1H), 5.03 (d, J = 12.8 Hz, 1H), 4.87 (s, 2H), 4.16(dt, J = 7.3, 5.8 Hz, 2H), 3.88 (d, J = 15.9 Hz, 1H), 3.44 (d, J = 15.8Hz, 1H), 2.69 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). LCMS Method F; t_(R):0.58 min; m/z: 422 [M + H] Example  90

(19R)-3-ethyl-14,16-difluoro-10,19-dimethyl-5,20- dioxa-4,10,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.80 (s, 1H), 7.61 (dd, J = 9.8, 1.6 Hz, 1H), 7.48 (d, J = 1.7Hz, 1H), 7.29 (td, J = 9.3, 2.5 Hz, 1H), 6.24 (d, J = 1.6 Hz, 1H), 5.99(s, 2H), 5.25 (q, J = 6.2 Hz, 1H), 3.94 (d, J = 16.0 Hz, 1H), 3.90 (s,3H), 3.09 (d, J = 14.2 Hz, 1H), 2.80- 2.56 (m, 2H), 1.69 (d, J = 6.2 Hz,3H), 1.12 (t, J = 7.5 Hz, 3H). LCMS Method F; t_(R): 0.98 min; m/z: 438[M + H] Example  91

(19R)-3-(cyclopropylmethyl)-16-fluoro-19-methyl-10-(trifluoromethyl)-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.92 (dd, J = 9.8, 2.9 Hz, 1H), 7.71 (s, 1H), 7.56-7.49 (m, 2H),7.33 (td, J = 8.3, 2.9 Hz, 1H), 6.76 (s, 1H), 6.27 (s, 2H), 6.04 (d, J =1.6 Hz, 1H), 5.09 (d, J = 4.7 Hz, 1H), 4.08-3.83 (m, 3H), 2.93 (d, J =16.2 Hz, 1H), 1.71 (d, J = 6.2 Hz, 3H), 1.18-1.07 (m, 1H), 0.50-0.34 (m,2H), 0.27 (td, J = 9.0, 4.8 Hz, 1H), 0.17-0.06 (m, 1H). LCMS Method H;t_(R): 1.47 min; m/z: 499 [M + H] Example  92

3-ethyl-16-fluoro-10-(trifluoromethyl)-20-oxa- 3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.84 (dd, J = 9.4, 2.9 Hz, 1H), 7.73 (s, 1H), 7.58-7.50 (m, 2H),7.38 (td, J = 8.4, 2.9 Hz, 1H), 6.72 (s, 1H), 6.25 (s, 2H), 6.04 (d, J =1.6 Hz, 1H), 5.22 (d, J = 13.6 Hz, 1H), 4.86 (d, J = 13.6 Hz, 1H),4.14-4.03 (m, 2H), 3.99 (d, J = 16.3 Hz, 1H), 2.97 (d, J = 16.1 Hz, 1H),1.32 (t, J = 7.2 Hz, 3H). LCMS Method F; t_(R): 1.17 min; m/z: 459 [M +H] Example  93

(19R)-3-ethyl-16-fluoro-19-methyl-20-oxa-11-thia- 3,4,5,10,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),9,13,15,17,21(25),22-decaen-22- amine 1H NMR (400MHz, CDCl3) δ 8.67 (s, 1H), 7.60 (s, 1H), 7.36 (dd, J = 9.4, 2.3 Hz,1H), 7.14 (ddd, J = 14.0, 11.3, 7.4 Hz, 2H), 6.50 (s, 1H), 5.41 (d, J =6.4 Hz, 1H), 4.89 (s, 2H), 4.39 (dt, J = 13.9, 6.8 Hz, 2H), 4.22 (d, J =15.5 Hz, 1H), 3.40 (d, J = 15.4 Hz, 1H), 1.79 (d, J = 6.3 Hz, 3H), 1.49(t, J = 7.3 Hz, 3H). LCMS Method H; t_(R): 0.89 min; m/z: 423 [M + H]Example  94

(19R)-22-amino-16-fluoro-5,19-dimethyl-20-oxa-9- thia-4,5,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8(12),10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR(400 MHz, DMSO) δ 9.25 (s, 1H), 7.71 (dd, J = 10.2, 2.3 Hz, 1H), 7.53(d, J = 1.8 Hz, 1H), 7.32- 7.21 (m, 2H), 6.16 (d, J = 1.8 Hz, 1H), 6.11(s, 2H), 5.06-4.97 (m, 1H), 4.53 (d, J = 16.6 Hz, 1H), 4.15 (s, 3H),3.58 (d, J = 16.2 Hz, 1H), 1.73 (d, J = 6.2 Hz, 3H). LCMS Method F;t_(R): 0.69 min; m/z: 433 [M + H] Example  95

(19R)-3-ethyl-16-fluoro-19-methyl-20-oxa-10-thia- 3,4,5,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 8.84 (d, J = 0.9 Hz, 1H), 7.74 (dd, J = 10.3, 2.6 Hz, 1H), 7.57(d, J = 1.8 Hz, 1H), 7.33 (dd, J = 8.6, 5.8 Hz, 1H), 7.24 (td, J = 8.4,2.7 Hz, 1H), 6.29 (s, 2H), 5.86 (d, J = 1.6 Hz, 1H), 5.12 (d, J = 4.6Hz, 1H), 4.37-4.26 (m, 2H), 4.11 (d, J = 16.6 Hz, 1H), 3.18 (d, J = 15.5 Hz, 1H), 1.74 (d, J = 6.2 Hz, 3H), 1.35 (t, J = 7.3 Hz, 3H). LCMSMethod A; t_(R): 1.15 min; m/z: 423 [M + H] Example  96

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(trifluoromethyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.71 (dd, J = 10.4, 2.6 Hz, 1H), 7.51-7.45 (m, 2H), 7.22-7.11(m, 2H), 6.31-6.20 (m, 3H), 5.36 (d, J = 6.4 Hz, 1H), 4.15- 4.09 (m,2H), 3.87 (s, 3H), 3.68 (s, 1H), 2.79 (d, J = 15.7 Hz, 1H), 1.72 (d, J =6.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H). LCMS Method F; t_(R): 1.23 min;m/z: 487 [M + H] Example  97

(19R)-22-amino-16-fluoro-5,10,19-trimethyl-20-oxa- 4,5,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, MeOD) δ 7.66-7.57 (m, 2H), 7.37 (dd, J = 8.7, 5.1 Hz, 1H),7.26-7.17 (m, 1H), 6.29-6.21 (m, 2H), 5.30-5.20 (m, 1H), 4.33-4.26 (m,1H), 4.17 (s, 3H), 3.42 (d, J = 16.9 Hz, 1H), 2.32 (s, 3H), 1.83 (d, J =6.3 Hz, 3H). LCMS Method F; t_(R): 0.73 min; m/z: 430 [M + H] Example 98

(19R)-3-ethyl-16-fluoro-10-methoxy-19-methyl-20- oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.80 (dd, J = 9.8, 2.9 Hz, 1H), 7.63 (s, 1H), 7.49 (d, J = 1.7Hz, 1H), 7.34 (dd, J = 8.7, 5.2 Hz, 1H), 7.23 (td, J = 8.4, 3.0 Hz, 1H),6.26-6.13 (m, 3H), 5.70 (s, 1H), 5.31 (d, J = 4.8 Hz, 1H), 4.16-3.99 (m,2H), 3.84 (d, J = 16.4 Hz, 1H), 3.79 (s, 3H), 2.84 (d, J = 16.0 Hz, 1H),1.72 (d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H). LCMS Method F;t_(R): 0.71 min; m/z: 435 [M + H] Example  99

(19R)-3-ethyl-16-fluoro-19-methyl-10,20-dioxa- 3,4,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 8.92 (s, 1H), 7.86- 7.81 (m, 1H), 7.63 (s, 1H), 7.45 (d, J = 1.7Hz, 1H), 7.29 (dd, J = 15.0, 4.2 Hz, 2H), 6.18 (s, 3H), 5.35- 5.29 (m,1H), 4.08-3.97 (m, 2H), 3.68 (d, J = 15.5 Hz, 1H), 2.57 (d, J = 15.8 Hz,1H), 1.72 (d, J = 6.3 Hz, 3H), 1.27 (d, J = 7.2 Hz, 3H). LCMS Method C;t_(R): 1.05 min; m/z: 406 [M + H] Example 100

(20R)-23-amino-17-fluoro-5,20-dimethyl-21-oxa- 4,5,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),3,8(13),9,11,14,16,18,22(26),23- undecaene-3-carbonitrile 1HNMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 4.6 Hz, 1H), 7.69 (d, J = 7.9 Hz,1H), 7.65 (dd, J = 10.3, 2.7 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.49(dd, J = 8.0, 4.7 Hz, 1H), 7.34 (dd, J = 8.5, 5.8 Hz, 1H), 7.23 (td, J =8.5, 2.7 Hz, 1H), 6.09 (s, 2H), 6.02 (d, J = 2.0 Hz, 1H), 5.01-4.91 (m,1H), 4.43 (d, J = 16.6 Hz, 1H), 4.20 (s, 3H), 3.39 (d, J = 16.6 Hz, 1H),1.74 (d, J = 6.2 Hz, 3H). LCMS Method G; t_(R): 3.05 min; m/z: 427 [M +H] Example 101

23-amino-17-fluoro-5-methyl-21-oxa-4,5,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),3,8(13),9,11,14,16,18,22(26),23- undecaene-3-carbonitrile 1HNMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 4.7 Hz, 1H), 7.68 (d, J = 8.0 Hz,1H), 7.61 (dd, J = 9.8, 2.6 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.48 (dd,J = 8.0, 4.7 Hz, 1H), 7.37 (dd, J = 8.6, 5.7 Hz, 1H), 7.27 (td, J = 8.5,2.8 Hz, 1H), 6.09 (s, 2H), 6.03 (d, J = 1.5 Hz, 1H), 5.23 (d, J = 13.6Hz, 1H), 4.71 (d, J = 13.7 Hz, 1H), 4.47 (d, J = 16.6 Hz, 1H), 4.20 (s,3H), 3.42-3.41 (m, 1H). LCMS Method C; t_(R): 1.32 min; m/z: 413 [M + H]Example 102

(19R)-10-(difluoromethyl)-3-ethyl-16-fluoro-19-methyl-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.89 (dd, J = 9.8, 2.9 Hz, 1H), 7.71 (s, 1H), 7.54-7.43 (m, 2H),7.35-7.27 (m, 1H), 7.04 (t, J = 52 Hz, 1H), 6.50 (s, 1H), 6.25 (s, 2H),6.02 (d, J = 1.5 Hz, 1H), 5.11 (d, J = 5.0 Hz, 1H), 4.07 (dt, J = 13.5,6.8 Hz, 2H), 3.93 (d, J = 16.3 Hz, 1H), 2.91 (d, J = 16.1 Hz, 1H), 1.71(d, J = 6.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H). LCMS Method H; t_(R):1.14 min; m/z: 455 [M + H] Example 103

(19R)-22-amino-10-chloro-16-fluoro-5,19-dimethyl- 20-oxa-4,5,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, DMSO-d6) δ 7.82 (dd, J = 9.6, 2.9 Hz, 1H), 7.53 (d, J = 1.8 Hz,1H), 7.47 (dd, J = 8.8, 5.1 Hz, 1H), 7.36 (td, J = 8.3, 3.0 Hz, 1H),6.70 (s, 1H), 6.18 (s, 2H), 6.06 (d, J = 1.7 Hz, 1H), 5.21-5.13 (m, 1H),4.43 (d, J = 17.1 Hz, 1H), 4.12 (s, 3H), 3.22 (d, J = 17.0 Hz, 1H), 1.71(d, J = 6.2 Hz, 3H). LCMS Method F; t_(R): 1.12 min; m/z: 450 [M + H]Example 104

(19R)-22-amino-16-fluoro-5,19-dimethyl-10-(trifluoromethyl)-20-oxa-4,5,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, DMSO) δ 7.87 (dd, J = 9.7, 2.9 Hz, 1H), 7.61-7.50 (m, 2H), 7.41(td, J = 8.4, 2.9 Hz, 1H), 7.10 (s, 1H), 6.21 (s, 2H), 5.97 (d, J = 1.6Hz, 1H), 5.08-4.96 (m, 1H), 4.51 (d, J = 17.3 Hz, 1H), 4.16 (s, 3H),3.30 (d, J = 17.1 Hz, 1H), 1.72 (d, J = 6.2 Hz, 3H). LCMS Method F;t_(R): 1.24 min; m/z: 484 [M + H] Example 105

(20R)-23-amino-10,17-difluoro-5,20-dimethyl-21- oxa-4,5,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),3,8(13),9,11,14,16,18,22(26),23- undecaene-3-carbonitrile 1HNMR (400 MHz, DMSO) δ 8.67 (d, J = 2.6 Hz, 1H), 7.66 (dd, J = 10.3, 2.7Hz, 1H), 7.55 (d, J = 1.9 Hz, 2H), 7.32 (dd, J = 8.5, 5.8 Hz, 1H), 7.24(td, J = 8.4, 2.7 Hz, 1H), 6.11 (s, 2H), 6.01 (d, J = 1.6 Hz, 1H),5.05-4.92 (m, 1H), 4.47 (d, J = 16.7 Hz, 1H), 4.19 (s, 3H), 3.33 (s,1H), 1.72 (d, J = 6.2 Hz, 3H). LCMS Method F; t_(R): 0.78 min; m/z: 445[M + H] Example 106

(20R)-3-(cyclopropylmethyl)-10,17-difluoro-20-methyl-21-oxa-3,4,5,12,24-pentaazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23- undecaen-23-amine 1H NMR(400 MHz, DMSO) δ 8.59 (d, J = 2.8 Hz, 1H), 7.73-7.64 (m, 2H), 7.62 (d,J = 1.8 Hz, 1H), 7.29 (dd, J = 8.5, 5.8 Hz, 1H), 7.18 (td, J = 8.4, 2.7Hz, 1H), 6.29 (s, 2H), 6.00 (d, J = 1.6 Hz, 1H), 5.14 (dd, J = 6.3, 1.7Hz, 1H), 4.29-4.13 (m, 3H), 3.28 (dd, J = 15.6, 1.5 Hz, 1H), 1.72 (d, J= 6.2 Hz, 3H), 1.16 (tt, J = 10.1, 3.8 Hz, 1H), 0.50-0.39 (m, 2H),0.36-0.29 (m, 1H), 0.23-0.15 (m, 1H). LCMS Method F; t_(R): 1.16 min;m/z: 461 [M + H] Example 107

(19R)-3-ethyl-16-fluoro-19-methyl-10-(trifluoromethyl)-20-oxa-3,4,5,11,12,23-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.89 (dd, J = 9.7, 2.9 Hz, 1H), 7.65-7.58 (m, 2H), 7.37 (td, J =8.4, 2.9 Hz, 1H), 6.65 (s, 1H), 6.39 (s, 2H), 5.99 (d, J = 1.5 Hz, 1H),5.10 (d, J = 5.0 Hz, 1H), 4.34 (ddd, J = 26.3, 14.2, 7.1 Hz, 3H), 3.21(d, J = 16.2 Hz, 1H), 1.72 (d, J = 6.2 Hz, 3H), 1.37 (t, J = 7.3 Hz,3H). LCMS Method F; t_(R): 1.32 min; m/z: 474 [M + H] Example 108

(19R)-10-chloro-3-(cyclopropylmethyl)-16-fluoro-19-methyl-20-oxa-3,4,5,11,12,23-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.84 (dd, J = 9.8, 2.9 Hz, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.50(dd, J = 8.8, 5.2 Hz, 1H), 7.32 (td, J = 8.3, 3.0 Hz, 1H), 6.35 (s, 2H),6.31 (s, 1H), 6.10 (d, J = 1.6 Hz, 1H), 5.25 (q, J = 6.0 Hz, 1H),4.30-4.15 (m, 3H), 3.14 (d, J = 16.1 Hz, 1H), 1.72 (d, J = 6.2 Hz, 3H),1.21-1.12 (m, 1H), 0.53- 0.40 (m, 2H), 0.32 (dt, J = 7.6, 4.7 Hz, 1H),0.20 (dq, J = 9.9, 4.8 Hz, 1H). LCMS Method F; t_(R): 1.26 min; m/z: 466[M + H] Example 109

(19R)-3-(cyclopropylmethyl)-16-fluoro-10,19-dimethyl-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO-d6) δ 7.80 (dd, J = 9.8, 3.0 Hz, 1H), 7.62 (s, 1H), 7.50 (d, J =1.7 Hz, 1H), 7.30 (dd, J = 8.7. 5.2 Hz, 1H), 7.25 (dd, J = 8.1, 2.8 Hz,1H), 6.19 (s, 2H), 6.10 (d, J = 1.9 Hz, 1H), 6.04 (s, 1H), 5.21 (d, J =6.4 Hz, 1H), 4.03-3.98 (m, 1H), 3.88 (d, J = 7.3 Hz, 1H), 3.84 (d, J =5.8 Hz, 1H), 2.84 (d, J = 16.0 Hz, 1H), 2.19 (s, 3H), 1.70 (d, J = 6.2Hz, 3H), 1.11 (s, 1H), 0.40 (ddd, J = 16.7, 8.9, 4.7 Hz, 2H), 0.25 (dd,J = 9.2, 4.6 Hz, 1H), 0.09 (dd, J = 9.2, 4.6 Hz, 1H). LCMS Method F;t_(R): 1.07 min; m/z: 445 [M + H] Example 110

10-chloro-3-(cyclopropylmethyl)-16-fluoro-20-oxa- 3,4,5,11,12,23-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.78 (dd, J = 9.4, 3.0 Hz, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.54(dd, J = 8.8, 5.1 Hz, 1H), 7.41-7.34 (m, 1H), 6.37 (s, 2H), 6.31 (s,1H), 6.10 (s, 1H), 5.21 (d, J = 13.6 Hz, 1H), 4.99 (d, J = 13.7 Hz, 1H),4.30-4.18 (m, 3H), 3.19 (d, J = 16.1 Hz, 1H), 1.19 (m, 1H), 0.54-0.42(m, 2H), 0.37- 0.30 (m, 1H), 0.23 (dd, J = 8.6, 4.0 Hz, 1H). LCMS MethodF; t_(R): 1.19 min; m/z: 452 [M + H] Example 111

(19R)-22-amino-16-fluoro-4,10,19-trimethyl-20-oxa- 4,5,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,5,8,11,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, DMSO) δ 7.64 (dd, J = 10.3, 2.6 Hz, 1H), 7.59 (s, 1H), 7.50 (d, J =1.8 Hz, 1H), 7.26- 7.16 (m, 2H), 6.32 (d, J = 1.6 Hz, 1H), 6.08 (s, 2H),5.32-5.18 (m, 1H), 4.00 (s, 3H), 3.93-3.84 (m, 4H), 2.98 (d, J = 15.3Hz, 1H), 1.72 (d, J = 6.2 Hz, 3H). LCMS Method F; t_(R): 0.84 min; m/z:430 [M + H] Example 112

(20R)-23-amino-17-fluoro-4,20-dimethyl-21-oxa- 4,5,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2,5,8(13),9,11,14,16,18,22(26),23-undecaene- 3-carbonitrile 1H NMR(400 MHz, CDCl3) δ 8.63 (d, J = 4.7 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H),7.49 (d, J = 1.6 Hz, 1H), 7.39-7.31 (m, 2H), 7.21-7.17 (m, 1H),7.14-7.10 (m, 1H), 6.41 (d, J = 1.3 Hz, 1H), 5.24-5.15 (m, 1H),4.17-4.09 (m, 4H), 3.57 (d, J = 15.5 Hz, 1H), 1.92 (d, J = 6.3 Hz, 3H).LCMS Method H; t_(R): 0.99 min; m/z: 427 [M + H] Example 113

22-amino-10-chloro-16-fluoro-5-methyl-20-oxa- 4,5,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, DMSO) δ 7.75 (dd, J = 9.4, 2.9 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H),7.51 (dd, J = 8.8, 5.2 Hz, 1H), 7.45-7.37 (m, 1H), 6.69 (s, 1H), 6.17(s, 2H), 6.07 (d, J = 1.7 Hz, 1H), 5.23 (d, J = 13.8 Hz, 1H), 4.91 (d, J= 14.2 Hz, 1H), 4.47 (d, J = 17.2 Hz, 1H), 4.14 (s, 3H), 3.29-3.26 (m,1H). LCMS Method H; t_(R): 1.05 min; m/z: 436 [M + H] Example 114

(19R)-3-(cyclopropylmethyl)-16-fluoro-10,19-dimethyl-20-oxa-9-thia-3,4,5,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400MHz, DMSO) δ 7.52-7.42 (m, 2H), 7.10 (dd, J = 8.4, 5.9 Hz, 1H), 7.02(td, J = 8.4, 2.7 Hz, 1H), 6.23 (s, 1H), 5.06 (d, J = 5.0 Hz, 1H),4.10-3.94 (m, 3H), 3.28 (s, 1H), 2.45 (s, 3H), 1.55 (d, J = 6.2 Hz, 3H),0.98-0.89 (m, 1H), 0.32-0.21 (m, 2H), 0.12 (dd, J = 9.6, 6.0 Hz, 1H),0.05-−0.05 (m, 1H). LCMS Method F; t_(R): 1.08 min; m/z: 463 [M + H]Example 115

22-amino-16-fluoro-5,10-dimethyl-20-oxa-9-thia- 4,5,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8(12),10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR(400 MHz, DMSO) δ 7.63 (d, J = 9.2 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H),7.35-7.25 (m, 2H), 6.33 (d, J = 1.7 Hz, 1H), 6.10 (s, 2H), 5.23 (d, J =13.2 Hz, 1H), 4.83 (d, J = 12.6 Hz, 1H), 4.47 (d, J = 16.4 Hz, 1H), 4.12(s, 3H), 3.54 (d, J = 14.7 Hz, 1H), 2.68 (s, 3H). LCMS Method F; t_(R):0.94 min; m/z: 433 [M + H] Example 116

(20R)-3-(cyclopropylmethyl)-17-fluoro-20-methyl- 21-oxa-3,4,5,12,24-pentaazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23- undecaen-23-amine 1H NMR(400 MHz, DMSO) δ 8.57 (dd, J = 4.6, 1.4 Hz, 1H), 7.95 (d, J = 7.2 Hz,1H), 7.69 (dd, J = 10.4, 2.7 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.47(dd, J = 7.9, 4.7 Hz, 1H), 7.30 (dd, J = 8.5, 5.8 Hz, 1H), 7.18 (td, J =8.4, 2.7 Hz, 1H), 6.28 (s, 2H), 6.00 (d, J = 1.6 Hz, 1H), 5.17-5.07 (m,1H), 4.29-4.13 (m, 3H), 3.28 (s, 1H), 1.75 (d, J = 6.2 Hz, 3H), 1.14 (s,1H), 0.49-0.38 (m, 2H), 0.34-0.27 (m, 1H), 0.18 (dd, J = 8.5, 4.0 Hz,1H). LCMS Method F; t_(R): 0.99 min; m/z: 443 [M + H] Example 117

(20R)-23-amino-17-fluoro-5,20-dimethyl-21-oxa- 4,5,24-triazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),3,8(13),9,11,14,16,18,22(26),23- undecaene-3-carbonitrile 1HNMR (400 MHz, DMSO) δ 7.62 (dd, J = 10.3, 2.7 Hz, 1H), 7.57 (s, 1H),7.50-7.45 (m, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.33-7.26 (m, 2H), 7.22 (t,J = 7.2 Hz, 2H), 6.13 (d, J = 1.7 Hz, 1H), 6.07 (s, 2H), 4.98 (d, J =6.7 Hz, 1H), 4.30 (d, J = 16.7 Hz, 1H), 4.18 (s, 3H), 3.36 (s, 1H), 1.77(d, J = 6.3 Hz, 3H). LCMS Method H; t_(R): 1.32 min; m/z: 426 [M + H]Example 118

(19R)-22-amino-16-fluoro-19-methyl-4-(propan-2- yl)-20-oxa-4,5,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,5,8,10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, DMSO) δ 7.82-7.69 (m, 2H), 7.56 (d, J = 1.8 Hz, 1H), 7.48 (dd, J =8.8, 5.2 Hz, 1H), 7.37-7.25 (m, 1H), 6.21 (d, J = 1.1 Hz, 1H), 6.16 (s,2H), 5.98 (d, J = 1.7 Hz, 1H), 5.20-5.04 (m, 1H), 4.84- 4.67 (m, 1H),4.21 (d, J = 16.1 Hz, 1H), 3.23 (d, J = 15.9 Hz, 1H), 1.73 (d, J = 6.2Hz, 3H), 1.55 (dd, J = 8.3, 6.7 Hz, 6H). LCMS Method F; t_(R): 1.18 min;m/z: 444 [M + H] Example 119

(19R)-22-amino-4-ethyl-16-fluoro-19-methyl-20- oxa-4,5,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,5,8,10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, DMSO) δ 7.77 (dd, J = 9.7, 2.9 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H),7.55 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 8.8, 5.2 Hz, 1H), 7.32 (td, J =8.3, 3.0 Hz, 1H), 6.24 (d, J = 1.1 Hz, 1H), 6.17 (s, 2H), 5.99 (d, J =1.6 Hz, 1H), 5.17-5.04 (m, 1H), 4.35 (q, J = 7.2 Hz, 2H), 4.21 (d, J =16.3 Hz, 1H), 3.23 (d, J = 15.9 Hz, 1H), 1.73 (d, J = 6.2 Hz, 3H), 1.48(t, J = 7.3 Hz, 3H). LCMS Method F; t_(R): 1.02 min; m/z: 430 [M + H]Example 120

(19R)-3-ethyl-16-fluoro-19-methyl-5,20-dioxa- 4,8,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,9,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,MeOD) δ 8.74 (s, 1H), 7.70 (dd, J = 10.0, 2.7 Hz, 1H), 7.53-7.38 (m,2H), 7.26 (td, J = 8.2, 2.7 Hz, 1H), 5.86 (d, J = 1.7 Hz, 1H), 5.57-5.50 (m, 1H), 5.47 (d, J = nce15.6 Hz, 1H), 4.79 (d, J = 15.6 Hz, 1H),2.87-2.61 (m, 2H), 1.88 (d, J = 6.3 Hz, 4H), 1.26-1.14 (m, 4H). LCMSMethod F; t_(R): 0.85 min; m/z: 407 [M + H] Example 121

(19R)-3-(cyclopropylmethyl)-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.68 (d, J = 9.9 Hz, 1H), 7.58 (d, J = 10.2 Hz, 2H), 7.45 (d, J= 1.7 Hz, 1H), 7.16-7.09 (m, 2H), 6.27 (d, J = 1.4 Hz, 1H), 6.07 (s,2H), 5.32 (d, J = 4.6 Hz, 1H), 3.95 (dd, J = 14.4, 6.1 Hz, 1H),3.86-3.77 (m, 4H), 3.58 (d, J = 15.6 Hz, 1H), 2.70 (d, J = 15.4 Hz, 1H),1.70 (d, J = 6.2 Hz, 3H), 1.13-1.01 (m, 1H), 0.44-0.32 (m, 2H), 0.23(td, J = 9.1, 4.9 Hz, 1H), 0.06 (td, J = 9.2, 5.0 Hz, 1H). LCMS MethodF; t_(R): 0.79 min; m/z: 445 [M + H] Example 122

(19R)-3-(cyclopropylmethyl)-10-(difluoromethyl)-16-fluoro-19-methyl-20-oxa-3,4,5,11,12,23-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO-d6) δ 7.86 (dd, J = 9.9, 2.9 Hz, 1H),7.65 (d, J = 1.8 Hz, 1H), 7.55(dd, J = 8.8, 5.1 Hz, 1H), 7.37-7.30 (m, 1H), 7.04 (t, J = 54.6 Hz, 1H),6.45 (s, 1H), 6.36 (s, 2H), 5.98 (s, 1H), 5.13 (d, J = 6.1 Hz, 1H), 4.30(s, 1H), 4.22 (dd, J = 12.3, 7.0 Hz, 2H), 3.17 (s, 1H), 1.72 (d, J = 6.2Hz, 3H), 1.17 (s, 1H), 0.50-0.43 (m, 2H), 0.36-0.30 (m, 1H), 0.20 (s,1H). LCMS Method H; t_(R): 1.12 min; m/z: 482 [M + H] Example 123

(20R)-23-amino-3-(cyclopropylmethyl)-17-fluoro-20-methyl-21-oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23- undecaene-5-carbonitrile 1HNMR (400 MHz, DMSO) δ 8.63 (dd, J = 4.6, 1.2 Hz, 1H), 7.65 (dd, J =10.3, 2.7 Hz, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H),7.48 (dd, J = 8.0, 4.7 Hz, 1H), 7.35 (dd, J = 8.5, 5.8 Hz, 1H), 7.24(td, J = 8.4, 2.7 Hz, 1H), 6.07 (s, 2H), 6.01 (d, J = 1.7 Hz, 1H),4.97-4.90 (m, 1H), 4.45 (d, J = 16.8 Hz, 1H), 4.40 (d, J = 7.1 Hz, 2H),3.38 (d, J = 16.7 Hz, 1H), 1.73 (d, J = 6.2 Hz, 3H), 1.43-1.36 (m, 1H),0.63- 0.41 (m, 4H). LCMS Method F; t_(R): 1.08 min; m/z: 467 [M + H]Example 124

(19R)-3-(cyclopropylmethyl)-16-fluoro-10-methoxy-5,19-dimethyl-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.78 (dd, J = 9.8, 3.0 Hz, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.35(dd, J = 8.7, 5.3 Hz, 1H), 7.26-7.17 (m, 1H), 6.22 (d, J = 1.5 Hz, 1H),6.15 (s, 2H), 5.67 (s, 1H), 5.32-5.22 (m, 1H), 3.95 (dd, J = 14.4, 6.0Hz, 1H), 3.84-3.69 (m, 5H), 2.30 (s, 3H), 2.78 (d, J = 16.3 Hz, 1H),1.71 (d, J = 6.2 Hz, 3H), 1.13-1.03 (m, 1H), 0.49-0.29 (m, 2H), 0.28-0.17 (m, 1H), 0.10-0.00 (m, 1H). LCMS Method F; t_(R): 1.17 min; m/z:475 [M + H] Example 125

(19R)-3-(cyclopropylmethyl)-10-(difluoromethyl)-16-fluoro-5,19-dimethyl-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,MeOD) δ 7.67 (dd, J = 9.5, 2.9 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.38(dd, J = 8.7, 5.1 Hz, 1H), 7.24-7.16 (m, 1H), 6.79 (t, J = 56 Hz, 1H),6.44 (s, 1H), 6.24 (d, J = 1.7 Hz, 1H), 5.23 (d, J = 4.4 Hz, 1H), 4.04(dd, J = 14.6, 6.1 Hz, 1H), 3.94-3.86 (m, 2H), 3.08 (d, J = 16.6 Hz,1H), 2.45 (s, 3H), 1.80 (d, J = 6.3 Hz, 3H), 1.12 (s, 1H), 0.46 (dd, J =19.1, 10.8 Hz, 2H), 0.27 (dd, J = 9.6, 4.7 Hz, 1H), 0.08 (dd, J = 9.8,4.6 Hz, 1H). LCMS Method H; t_(R): 1.39 min; m/z: 495 [M + H] Example126

3-(cyclopropylmethyl)-16-fluoro-10-methyl-20-oxa- 3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.75 (dd, J = 9.5, 2.8 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J = 1.8Hz, 1H), 7.37- 7.24 (m, 2H), 6.18 (s, 2H), 6.10 (d, J = 1.6 Hz, 1H),6.04 (s, 1H), 5.13 (d, J = 13.5 Hz, 1H), 4.98 (d, J = 14.3 Hz, 1H), 4.02(dd, J = 14.4, 6.1 Hz, 1H), 3.93- 3.78 (m, 2H), 2.95-2.83 (m, 1H), 2.20(s, 3H), 1.18- 1.05 (m, 1H), 0.49-0.34 (m, 2H), 0.32-0.21 (m, 1H),0.18-0.07 (m, 1H). LCMS Method F; t_(R): 0.68 min; m/z: 431 [M + H]Example 127

3-(cyclopropylmethyl)-16-fluoro-5,10-dimethyl-20- oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,MeOD) δ 7.54 (d, J = 7.6 Hz, 2H), 7.42 (s, 1H), 7.26-7.20 (m, 1H), 7.11(dd, J = 9.7, 7.3 Hz, 1H), 6.48 (s, 1H), 5.17 (s, 2H), 3.99-3.94 (m,1H), 3.92 (s, 3H), 3.89-3.85 (m, 1H), 3.59 (s, 1H), 2.91 (d, J = 15.8Hz, 1H), 2.44 (s, 3H), 1.06 (s, 1H), 0.49-0.43 (m, 1H), 0.37 (d, J = 4.7Hz, 1H), 0.24 (dd, J = 9.8, 4.8 Hz, 1H), 0.06-0.02 (m, 1H). LCMS MethodF; t_(R): 0.93 min; m/z: 445 [M + H] Example 128

(19R)-3-(cyclopropylmethyl)-16-fluoro-19-methyl-10-(trifluoromethyl)-20-oxa-3,4,5,11,12,23-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.89 (dd, J = 9.7, 2.9 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.60(dd, J = 8.8, 5.2 Hz, 1H), 7.37 (td, J = 8.3, 2.9 Hz, 1H), 6.67 (s, 1H),6.38 (s, 2H), 6.01 (d, J = 1.6 Hz, 1H), 5.11 (d, J = 4.8 Hz, 1H), 4.31(d, J = 15.9 Hz, 1H), 4.22 (ddd, J = 21.9, 14.6, 7.6 Hz, 2H), 3.22 (d, J= 16.2 Hz, 1H), 1.72 (d, J = 6.2 Hz, 3H), 1.18 (m, 1H), 0.56-0.38 (m,2H), 0.33 (dd, J = 8.7, 4.1 Hz, 1H), 0.21 (dd, J = 8.8, 4.1 Hz, 1H).LCMS Method G; t_(R): 2.92 min; m/z: 500 [M + H] Example 129

3-(cyclopropylmethyl)-16-fluoro-10-methyl-20-oxa- 3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO-d6) δ 7.64 (d, J = 9.5 Hz, 1H), 7.58 (d, J = 1.8 Hz, 2H), 7.47 (d,J = 1.7 Hz, 1H), 7.17 (d, J = 6.7 Hz, 2H), 6.28 (d, J = 1.9 Hz, 1H),6.08 (s, 2H), 5.07 (q, J = 13.1 Hz, 2H), 3.96 (dd, J = 14.4, 6.1 Hz,1H), 3.84 (s, 3H), 3.79 (d, J = 7.5 Hz, 1H), 3.59 (d, J = 15.4 Hz, 1H),2.74 (d, J = 15.4 Hz, 1H), 1.07 (d, J = 15.5 Hz, 1H), 0.40 (ddd, J =15.9, 8.8, 4.9 Hz, 2H), 0.24 (dt, J = 9.0, 4.9 Hz, 1H), 0.09 (dd, J =8.8, 4.4 Hz, 1H). LCMS Method F; t_(R): 0.99 min; m/z: 431 [M + H]Example 130

(19R)-3-(cyclopropylmethyl)-10-(difluoromethyl)-16-fluoro-19-methyl-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.88 (dd, J = 9.8, 2.9 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J = 1.7Hz, 1H), 7.46 (dd, J = 8.7, 5.2 Hz, 1H), 7.31 (td, J = 8.5, 2.9 Hz, 1H),7.10 (t, J = 54.7 Hz, 1H), 6.52 (s, 1H), 6.24 (s, 2H), 6.03 (s, 1H),5.11 (d, J = 6.1 Hz, 1H), 3.94 (ddd, J = 39.9, 14.4, 7.8 Hz, 3H), 2.91(d, J = 16.2 Hz, 1H), 1.72 (d, J = 6.2 Hz, 3H), 1.11 (d, J = 6.0 Hz,1H), 0.48- 0.35 (m, 2H), 0.26 (dd, J = 9.1, 4.2 Hz, 1H), 0.10 (dd, J =9.2, 4.5 Hz, 1H). LCMS Method F; t_(R): 1.49 min; m/z: 481 [M + H]Example 131

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-9,20-dioxa- 3,4,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400MHz, DMSO) δ 7.87 (s, 1H), 7.69 (s, 1H), 7.68-7.56 (m, 2H), 7.36 (d, J =1.8 Hz, 1H), 6.91 (td, J = 8.4, 2.8 Hz, 1H), 6.02 (s, 2H), 5.90 (s, 1H),4.25 (d, J = 16.1 Hz, 1H), 3.98 (dt, J = 13.5, 6.9 Hz, 2H), 3.51 (d, J =16.5 Hz, 1H), 2.42 (s, 3H), 1.67 (d, J = 6.1 Hz, 3H), 1.25 (t, J = 7.2Hz, 3H). LCMS Method F; t_(R): 0.79 min; m/z: 420 [M + H] Example 132

(19R)-22-amino-10-(difluoromethyl)-16-fluoro-5,19-dimethyl-20-oxa-4,5,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,10,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, DMSO) δ 7.84 (d, J = 6.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 2H), 7.39(td, J = 8.3, 3.0 Hz, 1H), 7.07 (t, J = 54.4 Hz, 1H), 6.82 (s, 1H), 6.17(s, 2H), 5.96 (d, J = 1.7 Hz, 1H), 5.06 (d, J = 5.0 Hz, 1H), 4.49 (d, J= 17.2 Hz, 1H), 4.15 (s, 3H), 3.26 (s, 1H), 1.72 (d, J = 6.2 Hz, 3H).LCMS Method F; t_(R): 0.95 min; m/z: 466 [M + H] Example 133

(19R)-5-chloro-3-(cyclopropylmethyl)-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁹]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.70 (dd, J = 10.3, 2.5 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J = 1.8Hz, 1H), 7.22- 7.11 (m, 2H), 6.26 (s, 1H), 6.21 (s, 2H), 5.32 (d, J =6.2 Hz, 1H), 3.95 (dd, J = 14.4, 6.2 Hz, 1H), 3.87 (s, 3H), 3.82-3.75(m, 1H), 3.54 (d, J = 15.6 Hz, 1H), 2.74-2.67 (m, 1H), 1.71 (d, J = 6.3Hz, 3H), 1.09 (s, 1H), 0.50-0.34 (m, 2H), 0.25 (dd, J = 9.3, 4.4 Hz,1H), 0.12-0.04 (m, 1H). LCMS Method F; t_(R): 1.35 min; m/z: 479 [M + H]Example 134

(19R)-3-(cyclopropylmethyl)-16-fluoro-5,10,19-trimethyl-20-oxa-9-thia-3,4,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400MHz, DMSO) δ 7.65 (dd, J = 10.3, 2.6 Hz, 1H), 7.37 (d, J = 1.7 Hz, 1H),7.17-7.05 (m, 2H), 6.22 (d, J = 1.6 Hz, 1H), 6.05 (s, 2H), 5.12-5.04 (m,1H), 3.84 (dd, J = 14.4, 6.0 Hz, 1H), 3.75 (d, J = 15.9 Hz, 1H), 3.68(dd, J = 14.4, 7.4 Hz, 1H), 3.03 (d, J = 15.9 Hz, 1H), 2.57 (s, 3H),2.23 (s, 3H), 1.64 (d, J = 6.2 Hz, 3H), 1.06-0.94 (m, 1H), 0.39-0.25 (m,2H), 0.17-0.10 (m, 1H), −0.01 (dq, J = 9.6, 4.9 Hz, 1H). LCMS Method F;t_(R): 0.90 min; m/z: 476 [M + H] Example 135

(20R)-3-(cyclopropylmethyl)-17-fluoro-5,20- dimethyl-21-oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23- undecaen-23-amine 1H NMR(400 MHz, DMSO) δ 8.60-8.49 (m, 1H), 7.68 (dd, J = 10.3, 2.5 Hz, 2H),7.48-7.42 (m, 2H), 7.27 (dd, J = 8.5, 5.8 Hz, 1H), 7.15 (td, J = 8.4,2.7 Hz, 1H), 6.11 (s, 2H), 6.02 (d, J = 1.6 Hz, 1H), 5.04 (d, J = 4.6Hz, 1H), 3.99 (dd, J = 14.3, 5.9 Hz, 1H), 3.79 (dd, J = 14.6, 7.4 Hz,2H), 3.02 (d, J = 15.9 Hz, 1H), 2.39 (s, 3H), 1.72 (d, J = 6.2 Hz, 3H),1.13-1.04 (m, 1H), 0.45-0.31 (m, 2H), 0.22 (td, J = 9.2, 5.0 Hz, 1H),0.06 (td, J = 9.2, 5.0 Hz, 1H). LCMS Method H; t_(R): 0.93 min; m/z: 456[M + H] Example 136

3-(cyclopropylmethyl)-10-(difluoromethyl)-16-fluoro-5-methyl-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,MeOD) δ 7.68 (dd, J = 9.2, 2.9 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.41(dd, J = 8.8, 5.0 Hz, 1H), 7.25 (dd, J = 7.9, 3.0 Hz, 1H), 6.79 (t, J =54.9 Hz, 1H), 6.44 (s, 1H), 6.20 (d, J = 1.8 Hz, 1H), 5.19 (d, J = 13.8Hz, 1H), 5.02 (d, J = 15.0 Hz, 1H), 4.03 (d, J = 6.2 Hz, 1H), 3.92 (t, J= 11.4 Hz, 2H), 3.12 (d, J = 16.4 Hz, 1H), 2.45 (s, 3H), 1.12 (s, 1H),0.47 (d, J = 20.9 Hz, 2H), 0.27 (s, 1H), 0.10 (dt, J = 9.9, 5.0 Hz, 1H).LCMS Method H; t_(R): 1.07 min; m/z: 481 [M + H] Example 137

(20R)-3-(cyclopropylmethyl)-17-fluoro-20-methyl- 21-oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23- undecaen-23-amine 1H NMR(400 MHz, DMSO) δ 8.55-8.51 (m, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.77 (s,1H), 7.69 (dd, J = 10.4, 2.7 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.45(dd, J = 7.9, 4.7 Hz, 1H), 7.23-7.11 (m, 2H), 6.14 (s, 2H), 6.01 (d, J =1.5 Hz, 1H), 5.13 (d, J = 6.4 Hz, 1H), 4.02 (dd, J = 14.4, 6.0 Hz, 1H),3.91-3.78 (m, 2H), 3.09 (d, J = 15.4 Hz, 1H), 1.74 (d, J = 6.2 Hz, 3H),1.14- 1.04 (m, 1H), 0.46-0.31 (m, 2H), 0.23 (dd, J = 9.1, 4.2 Hz, 1H),0.07 (dt, J = 9.4, 4.7 Hz, 1H). LCMS Method K; t_(R): 1.05 min; m/z: 442[M + H] Example 138

3-(cyclopropylmethyl)-10-(difluoromethyl)-16-fluoro-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.82 (dd, J = 9.4, 2.9 Hz, 1H), 7.72 (s, 1H), 7.55 (d, J = 1.8Hz, 1H), 7.49 (dd, J = 8.8, 5.2 Hz, 1H), 7.39-7.31 (m, 1H), 7.03 (t, J =54.6 Hz, 1H), 6.51 (s, 1H), 6.25 (s, 2H), 6.02 (d, J = 1.7 Hz, 1H), 5.18(d, J = 13.6 Hz, 1H), 4.89 (d, J = 14.4 Hz, 1H), 4.06-3.84 (m, 3H), 2.95(d, J = 16.1 Hz, 1H), 1.20-1.07 (m, 1H), 0.51-0.35 (m, 2H), 0.27 (td, J= 9.0, 4.9 Hz, 1H), 0.12 (td, J = 9.2, 5.0 Hz, 1H). LCMS Method H;t_(R): 0.97 min; m/z: 467 [M + H] Example 139

(19R)-16-fluoro-10,19-dimethyl-3-(oxetan-3-yl)-20- oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.75 (s, 1H), 7.68 (d, J = 10.1 Hz, 1H), 7.58 (s, 1H), 7.24 (d,J = 1.7 Hz, 1H), 7.17-7.12 (m, 2H), 6.27 (s, 1H), 6.15 (s, 2H), 5.47 (t,J = 7.1 Hz, 1H), 5.32 (d, J = 4.7 Hz, 1H), 4.95-4.89 (m, 2H), 4.87 (t, J= 6.4 Hz, 1H), 4.64 (dd, J = 7.6, 6.1 Hz, 1H), 3.85 (d, J = 4.9 Hz, 3H),3.62 (d, J = 15.7 Hz, 1H), 2.71 (d, J = 15.4 Hz, 1H), 1.70 (d, J = 6.2Hz, 3H). LCMS Method L; t_(R): 2.03 min; m/z: 447 [M + H] Example 140

(19R)-3-(cyclopropylmethyl)-10-ethyl-16-fluoro-19-methyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.69 (dd, J = 10.3, 2.0 Hz, 1H), 7.63 (s, 1H), 7.57 (s, 1H),7.45 (d, J = 1.7 Hz, 1H), 7.19-7.09 (m, 2H), 6.25 (s, 1H), 6.07 (s, 2H),5.28 (d, J = 8.2 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.96 (dd, J = 14.2,6.0 Hz, 1H), 3.81 (dd, J = 14.4, 7.3 Hz, 1H), 3.59 (d, J = 15.6 Hz, 1H),2.72 (d, J = 15.5 Hz, 1H), 1.71 (d, J = 6.2 Hz, 3H), 1.37 (t, J = 7.2Hz, 3H), 1.08 (t, J = 11.7 Hz, 1H), 0.39 (dd, J = 24.4, 8.6 Hz, 2H),0.26-0.18 (m, 1H), 0.08 (t, J = 9.1 Hz, 1H). LCMS Method F; t_(R): 1.10min; m/z: 459 [M + H] Example 141

(19R)-3-(cyclopropylmethyl)-16-fluoro-5,10,19-trimethyl-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.79 (dd, J = 9.8, 2.9 Hz, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.32(dd, J = 8.7, 5.3 Hz, 1H), 7.23 (td, J = 8.3, 2.9 Hz, 1H), 6.15 (s, 2H),6.11 (d, J = 1.5 Hz, 1H), 6.02 (s, 1H), 5.18 (d, J = 4.7 Hz, 1H), 3.94(dd, J = 14.4, 6.0 Hz, 1H), 3.83-3.71 (m, 2H), 2.80 (d, J = 16.2 Hz,1H), 2.32 (s, 3H), 2.20 (s, 3H), 1.70 (d, J = 6.2 Hz, 3H), 1.14-1.03 (m,1H), 0.45-0.32 (m, 2H), 0.27-0.18 (m, 1H), 0.12-0.03 (m, 1H). LCMSMethod H; t_(R): 1.04 min; m/z: 459 [M + H] Example 142

(19R)-5-chloro-3-ethyl-16-fluoro-10,19-dimethyl-20- oxa-3,4,10,11,14,23-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,MeOD) δ 8.46 (d, J = 2.8 Hz, 1H), 8.12 (dd, J = 9.3, 2.8 Hz, 1H), 7.60(s, 1H), 7.45 (s, 1H), 6.48 (d, J = 1.6 Hz, 1H), 5.61-5.44 (m, 1H),4.19-3.98 (m, 2H), 3.95 (s, 3H), 3.71 (d, J = 16.0 Hz, 1H), 2.87 (d, J =16.0 Hz, 1H), 1.86 (d, J = 6.3 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H). LCMSMethod H; t_(R): 1.02 min; m/z: 454 [M + H] Example 143

(19R)-22-amino-16-fluoro-5,19-dimethyl-20-oxa-10- thia-4,5,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decaene-3- carbonitrile 1H NMR (400MHz, DMSO) δ 9.11 (s, 1H), 7.71 (dd, J = 10.3, 2.5 Hz, 1H), 7.52 (d, J =1.7 Hz, 1H), 7.38- 7.22 (m, 2H), 6.10 (s, 2H), 5.87 (s, 1H), 5.07-4.93(m, 1H), 4.39-4.24 (d, J = 16.7 Hz, 1H), 4.19 (s, 3H), 3.27 (d, J = 16.7Hz, 1H), 1.74 (t, J = 6.1 Hz, 3H). LCMS Method K; t_(R): 1.09 min; m/z:433 [M + H] Example 144

(19R)-3-(cyclopropylmethyl)-16-fluoro-10-methoxy-19-methyl-20-oxa-3,4,5,11,12,23-hexaazapentacyclo[19.3.1,0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.78 (dd, J = 9.7, 2.9 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.41(dd, J = 8.7, 5.2 Hz, 1H), 7.32-7.19 (m, 1H), 6.31 (s, 2H), 6.17 (s,1H), 5.68 (s, 1H), 5.39-5.28 (m, 1H), 4.32-4.10 (m, 3H), 3.79 (s, 3H),3.11 (d, J = 16.0 Hz, 1H), 1.73 (d, J = 6.2 Hz, 3H), 1.22-1.07 (m, 1H),0.52-0.37 (m, 2H), 0.34-0.26 (m, 1H), 0.23-0.12 (m, 1H). LCMS Method F;t_(R): 1.07 min; m/z: 462 [M + H] Example 145

(20R)-3-ethyl-17-fluoro-11-methoxy-20-methyl-21- oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23- undecaen-23-amine 1H NMR(400 MHz, DMSO-d6) δ 7.78 (d, J = 8.7 Hz, 1H), 7.74 (s, 1H), 7.69 (dd, J= 10.4, 2.7 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 8.5, 5.9Hz, 1H), 7.14 (td, J = 8.5, 2.7 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.17(d, J = 1.9 Hz, 1H), 6.12 (s, 2H), 5.27 (d, J = 6.3 Hz, 1H), 4.09-4.00(m, 2H), 3.82 (s, 3H), 3.73 (d, J = 15.4 Hz, 1H), 3.06 (d, J = 15.3 Hz,1H), 1.78 (d, J = 6.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H). LCMS Method H;t_(R): 1.13 min; m/z: 446 [M + H] Example 146

(20R)-3-(cyclopropylmethyl)-17-fluoro-20-methyl- 21-oxa-5,6,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2,4,8(13),9,11,14,16,18,22(26),23-undecaen- 23-amine 1H NMR (400MHz, DMSO) δ 8.64 (dd, J = 4.7, 1.4 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H),7.72 (dd, J = 10.4, 2.6 Hz, 1H), 7.58 (s, 1H), 7.51 (dd, J = 8.0, 4.7Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.26 (dd, J = 8.5, 5.8 Hz, 1H), 7.15(td, J = 8.4, 2.7 Hz, 1H), 6.14 (s, 2H), 6.05 (d, J = 1.6 Hz, 1H), 5.41(d, J = 16.0 Hz, 1H), 5.15 (dd, J = 6.3, 1.7 Hz, 1H), 4.45 (d, J = 15.9Hz, 1H), 2.29 (ddd, J = 39.9, 15.2, 6.7 Hz, 2H), 1.75 (d, J = 6.2 Hz,3H), 0.92-0.78 (m, 1H), 0.47-0.32 (m, 2H), 0.15- −0.03 (m, 2H). LCMSMethod H; t_(R): 1.23 min; m/z: 442 [M + H] Example 147

(19R)-10-(difluoromethyl)-3-ethyl-16-fluoro-5-methoxy-19-methyl-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.86 (dd, J = 9.8, 2.9 Hz, 1H), 7.54-7.47 (m, 2H), 7.34-7.27 (m,1H), 7.04 (t, J = 54.6 Hz, 1H), 6.47 (s, 2H), 6.41 (s, 1H), 6.06 (d, J =1.4 Hz, 1H), 5.10 (s, 1H), 3.94 (m, 5H), 3.79 (d, J = 16.5 Hz, 1H), 2.77(d, J = 16.2 Hz, 1H), 1.71 (d, J = 6.2 Hz, 3H), 1.26 (t, J = 7.1 Hz,3H). LCMS Method H; t_(R): 1.42 min; m/z: 485 [M + H] Example 148

(19R)-5-bromo-3-ethyl-16-fluoro-10,19-dimethyl-20- oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.70 (d, J = 10.6 Hz, 1H), 7.57 (s, 1H), 7.47 (s, 1H), 7.17 (t,J = 7.4 Hz, 2H), 6.28 (m, 3H), 5.33 (s, 1H), 4.07-3.96 (m, 2H), 3.87 (s,3H), 3.51 (d, J = 15.8 Hz, 1H), 2.71 (d, J = 15.5 Hz, 1H), 1.71 (d, J =6.3 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H). LCMS Method K; t_(R): 1.15 min;m/z: 497 [M + H] Example 149

(20R)-3-ethyl-17-fluoro-10-methoxy-20-methyl-21- oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23- undecaen-23-amine 1H NMR(400 MHz, DMSO) δ 8.28 (d, J = 2.8 Hz, 1H), 7.82 (s, 1H), 7.66 (dd, J =10.4, 2.6 Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 2.6 Hz, 1H),7.18- 7.09 (m, 2H), 6.13 (s, 2H), 6.03 (d, J = 1.6 Hz, 1H), 5.14 (d, J =4.5 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.80 (d, J = 15.6Hz, 1H), 3.06 (d, J = 15.4 Hz, 1H), 1.73 (d, J = 6.2 Hz, 3H), 1.29 (t, J= 7.2 Hz, 3H). LCMS Method F; t_(R): 1.32 min; m/z: 446 [M + H] Example150

(19R)-10-tert-butyl-3-ethyl-16-fluoro-19-methyl-20- oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.71 (dd, J = 10.4, 2.6 Hz, 1H), 7.62 (s, 1H), 7.59 (s, 1H),7.42 (d, J = 1.8 Hz, 1H), 7.16 (ddd, J = 11.0, 8.5, 4.4 Hz, 2H), 6.23(d, J = 1.6 Hz, 1H), 6.09 (s, 2H), 5.21 (d, J = 4.7 Hz, 1H), 4.00 (q, J= 7.2 Hz, 2H), 3.61 (d, J = 15.7 Hz, 1H), 2.77 (d, J = 15.4 Hz, 1H),1.71 (d, J = 6.3 Hz, 3H), 1.53 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H). LCMSMethod F; t_(R): 1.02 min; m/z: 461 [M + H] Example 151

(20R)-3-ethyl-17-fluoro-9-methoxy-20-methyl-21- oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0²,⁶.0⁸,¹³.0¹⁴,¹⁹]hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23- undecaen-23-amine 1H NMR(400 MHz, DMSO) δ 8.41 (s, 1H), 7.68- 7.63 (m, 2H), 7.40 (d, J = 1.8 Hz,1H), 7.05-7.08 (m, 3H), 6.31 (d, J = 1.6 Hz, 1H), 6.08 (s, 2H), 5.47 (d,J = 6.3 Hz, 1H), 3.98 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.87 (d, J =15.0 Hz, 1H), 3.19 (d, J = 14.9 Hz, 1H), 1.79 (d, J = 6.2 Hz, 3H), 1.26(s, 3H). LCMS Method K; t_(R): 0.60 min; m/z: 446 [M + H] Example 152

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-4,20-dioxa- 5,10,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,5,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz, DMSO)δ 7.72-7.66 (m, 1H), 7.66 (s, 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.26-7.11(m, 2H), 6.21 (d, J = 1.7 Hz, 1H), 5.98 (s, 2H), 5.33 (dt, J = 6.4, 3.2Hz, 1H), 3.92 (s, 1H), 3.88 (s, 3H), 2.91 (d, J = 15.0 Hz, 1H),2.80-2.66 (m, 2H), 1.72 (d, J = 6.3 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3H).LCMS Method F; t_(R): 0.98 min; m/z: 420 [M + H] Example 153

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(propan-2-yl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1,0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.67 (dd, J = 10.4, 2.5 Hz, 1H), 7.48 (s, 2H), 7.21 (dd, J =10.6, 4.4 Hz, 2H), 6.48 (s, 1H), 5.42 (d, J = 5.2 Hz, 1H), 3.98 (dd, J =14.5, 7.3 Hz, 2H), 3.87 (s, 3H), 3.60 (d, J = 16.1 Hz, 1H), 3.20-3.13(m, 1H), 2.70 (d, J = 16.0 Hz, 1H), 1.74 (d, J = 6.2 Hz, 3H), 1.44 (d, J= 6.8 Hz, 3H), 1.23 (d, J = 7.3 Hz, 6H). LCMS Method I; t_(R): 1.32 min;m/z: 461 [M + H] Example 154

(19R)-16-fluoro-10,19-dimethyl-3-(2-methylpropyl)- 20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.70 (d, J = 10.3 Hz, 1H), 7.57 (d, J = 2.8 Hz, 2H), 7.42 (d, J= 1.7 Hz, 1H), 7.16-7.10 (m, 2H), 6.25 (d, J = 1.5 Hz, 1H), 6.06 (s,2H), 5.31 (d, J = 4.7 Hz, 1H), 3.88-3.78 (m, 5H), 3.57 (d, J = 15.6 Hz,1H), 2.69 (d, J = 15.4 Hz, 1H), 1.99 (d, J = 6.9 Hz, 1H), 1.70 (d, J =6.3 Hz, 3H), 0.74 (d, J = 6.7 Hz, 3H), 0.61 (d, J = 6.6 Hz, 3H). LCMSMethod H; t_(R): 0.76 min; m/z: 447 [M + H] Example 155

(19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-5- thia-4,10,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,MeOD) δ 7.52 (dd, J = 6.3, 3.7 Hz, 2H), 7.47 (d, J = 1.8 Hz, 1H), 7.28(d, J = 5.7 Hz, 1H), 7.13 (s, 1H), 6.69 (d, J = 1.7 Hz, 1H), 5.34-5.28(m, 1H), 3.93 (s, 3H), 3.85 (d, J = 16.0 Hz, 1H), 3.14 (d, J = 15.9 Hz,1H), 3.05 (d, J = 7.5 Hz, 2H), 1.82 (d, J = 6.3 Hz, 3H), 1.44 (t, J =7.5 Hz, 3H). LCMS Method K; t_(R): 1.25 min; m/z: 436 [M + H] Example156

(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl- 20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaene-5- carbonitrile 1H NMR (400MHz, DMSO) δ 7.71 (dd, J = 10.4, 2.6 Hz, 1H), 7.64 (s, 1H), 7.53 (d, J =1.8 Hz, 1H), 7.27- 7.10 (m, 2H), 6.34-6.20 (m, 3H), 5.38-5.27 (m, 1H),4.20-4.10 (m, 2H), 3.88 (s, 3H), 3.71 (d, J = 15.9 Hz, 1H), 2.83 (d, J =15.7 Hz, 1H), 1.72 (d, J = 6.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H). LCMSMethod F; t_(R): 1.13 min; m/z: 444 [M + H] Example 157

(19R)-3-ethyl-16-fluoro-9-methoxy-10,19-dimethyl- 20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO-d6) δ 7.72-7.65 (m, 1H), 7.56 (s, 1H), 7.40 (d, J = 1.9 Hz, 1H),7.12 (dd, J = 7.5, 2.4 Hz, 2H), 6.39 (d, J = 1.9 Hz, 1H), 6.06 (s, 2H),5.55-5.45 (m, 1H), 4.09-3.94 (m, 2H), 3.72 (s, 3H), 3.66 (s, 3H), 3.61(d, J = 15.7 Hz, 1H), 2.74 (d, J = 15.6 Hz, 1H), 1.71 (d, J = 6.2 Hz,3H), 1.22 (t, J = 7.2 Hz, 3H). LCMS Method K; t_(R): 0.79 min; m/z: 449[M + H] Example 158

(19R)-3,5-diethyl-16-fluoro-10,19-dimethyl-20-oxa- 3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,CDCl3) δ 7.50 (d, J = 1.6 Hz, 1H), 7.30 (dd, J = 9.8, 2.6 Hz, 1H), 7.24(s, 1H), 7.14 (dd, J = 8.5, 5.8 Hz, 1H), 7.00 (td, J = 8.3, 2.7 Hz, 1H),6.51 (s, 1H), 5.40 (dd, J = 8.5, 4.0 Hz, 1H), 4.81 (s, 2H), 4.09 (tt, J= 13.7, 7.0 Hz, 2H), 3.92 (s, 3H), 3.54 (d, J = 15.9 Hz, 1H), 2.90 (d, J= 15.9 Hz, 1H), 2.82 (q, J = 7.6 Hz, 2H), 1.79 (d, J = 6.3 Hz, 3H), 1.38(dd, J = 13.2, 7.3 Hz, 6H). LCMS Method K; t_(R): 1.08 min; m/z: 447[M + H] Example 159

(19R)-16-fluoro-10,19-dimethyl-3-[(1-methylcyclopropyl)methyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,DMSO) δ 7.69 (d, J = 10.2 Hz, 1H), 7.58 (d, J = 7.7 Hz, 2H), 7.42 (d, J= 1.6 Hz, 1H), 7.16-7.08 (m, 2H), 6.26 (d, J = 1.4 Hz, 1H), 6.07 (s,2H), 5.31 (d, J = 4.6 Hz, 1H), 4.09 (d, J = 14.3 Hz, 1H), 3.85 (s, 3H),3.82 (d, J = 14.3 Hz, 1H), 3.57 (d, J = 15.6 Hz, 1H), 2.70 (d, J = 15.4Hz, 1H), 1.70 (d, J = 6.2 Hz, 3H), 0.73 (s, 3H), 0.50 (dt, J = 9.4, 4.7Hz, 1H), 0.25-0.17 (m, 1H), 0.15-0.03 (m, 2H). LCMS Method F; t_(R):0.96 min; m/z: 459 [M + H] Example 160

(19R)-3-(cyclopropylmethyl)-10-(difluoromethyl)-16-fluoro-19-methyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22- amine 1H NMR (400 MHz,CDCl3) δ 7.78-7.71 (m, 1H), 7.67 (s, 1H), 7.59 (s, 1H), 7.41 (d, J = 9.5Hz, 1H), 7.13 (dd, J = 13.8, 11.1 Hz, 2H), 6.94 (d, J = 59.4 Hz, 1H),6.73 (s, 1H), 5.18 (d, J = 6.0 Hz, 1H), 4.96 (s, 2H), 4.13 (dd, J =14.2, 6.1 Hz, 1H), 3.92 (dd, J = 14.3, 7.0 Hz, 1H), 3.55 (d, J = 15.7Hz, 1H), 2.90 (d, J = 15.7 Hz, 1H), 1.81-1.73 (m, 3H), 1.78 (m, 1H),0.53 (d, J = 8.0 Hz, 2H), 0.32 (d, J = 4.2 Hz, 1H), 0.18 (s, 1H). LCMSMethod K; t_(R): 1.22 min; m/z: 481 [M + H] Example 161

(19R)-3-ethyl-16-fluoro-9,19-dimethyl-11,20-dioxa- 3,4,10,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),9,13,15,17,21(25),22-decaen-22- amine 1H NMR (400MHz, DMSO) δ 7.89 (dd, J = 10.2, 2.2 Hz, 1H), 7.68 (s, 1H), 7.42 (d, J =1.7 Hz, 1H), 7.33- 7.19 (m, 2H), 6.49 (d, J = 1.5 Hz, 1H), 6.15 (s, 2H),5.28-5.12 (m, 1H), 4.09-3.89 (m, 2H), 3.69 (d, J = 15.7 Hz, 1H), 2.94(d, J = 15.6 Hz, 1H), 2.27 (s, 3H), 1.76 (d, J = 6.2 Hz, 3H), 1.26 (t, J= 7.2 Hz, 3H). LCMS Method F; t_(R): 1.01 min; m/z: 420 [M + H]

Example 162 (Method E)

-   -   Name:        (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5,20-dioxa-4,10,11,23,25-pentaazapentacyclo[19.3.1.0²,6.0^(8,12).0^(13,18)]pentacosa-1(24),2(6),        3,8,11,13,15,17,21(25),22-decaen-22-amine    -   NMR: 1H NMR (400 MHz, DMSO) δ 7.61 (dd, J=10.1, 2.3 Hz, 1H),        7.58 (s, 1H), 7.54 (s, 1H), 7.17 (m, 2H), 6.53 (s, 2H), 5.71        5.60 (in, TH), 3.82 (s, 3H), 3.77 (d, J=15.5 Hz, 1H), 3.23 (d,        J=15.1 Hz, 1H), 2.77 (dq, J=14.9, 7.4 Hz, 1H), 2.63 (dq, J=15.1,        7.5 Hz, 1H), 1.60 (d, J=6.6 Hz, 3H), 1.14 (t, J=7.5 Hz, 3H).    -   LCMS: Method F; t_(R): 1.15 min; m/z: 421 [M+H]

To a solution of(1R)-1-(2-{4-[(3-ethyl-1,2-oxazol-5-yl)methyl]-1-methyl-1H-pyrazol-3-yl}-5-fluorophenyl)ethan-1-ol(0.12 g, 0.36 mmol) in THF (7 mL) was added NaH (70 mg, 1.8 mmol, 60% inmineral oil) at 0° C. After stirring at 0° C. for 1 h, a solution of5-bromo-3-chloropyrazin-2-amine (75 mg, 0.36 mmol) in THF (1 mL) wasadded. Stirring was continued at 70° C. for 16 h. The mixture wasquenched with sat. aq. NH₄Cl and extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated. The residue was purified by flashchromatography (0→30% EA in PE) to give(R)-5-bromo-3-(1-(2-(4-((3-ethylisoxazol-5-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-5-fluorophenyl)ethoxy)pyrazin-2-amine(120 mg, 62% yield) as a yellow solid. LC-MS (ESI): 501 [M+H]⁺.

A mixture of5-bromo-3-[(1R)-1-(2-{4-[(3-ethyl-1,2-oxazol-5-yl)methyl]-1-methyl-1H-pyrazol-3-yl}-5-fluorophenyl)ethoxy]pyrazin-2-amine(120 mg, 0.24 mmol), potassium acetate (120 mg, 1.22 mmol), cataCXium A(35 mg, 0.10 mmol) and Pd(OAc)₂ (10 mg, 0.05 mmol) in 2-methyl-2-butanol(12 mL) was stirred at 120° C. for 6 h under N₂. The reaction wasfiltered, and the filtrate was dissolved in EtOAc (30 mL). This solutionwas washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered,and concentrated. The residue was purified by flash chromatography(0→80% EtOAc in PE) followed by prep-HPLC (XBridge C18 OBD 250*19 mm 5um, MeCN in H₂O+0.1% FA) to afford the target product (24.0 mg, 24%yield) as an off-white solid. LC/MS (ESI) m/z: 421 [M+H]⁺.

The following compounds were prepared in a similar manner:

Example 163

3-ethyl-16-fluoro-19-methyl-20-oxa-3,4,8,11,23,25-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,9,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.89 (s, 1H), 7.66 (dd, J = 10.1, 2.7 Hz, 1H), 7.59 (s, 1H),7.34 (dd, J = 8.5, 5.8 Hz, 1H), 7.20 (td, J = 8.5, 2.7 Hz, 1H), 7.13 (d,J = 1.2 Hz, 1H), 6.96 (d, J = 1.1 Hz, 1H), 6.76 (s, 2H), 5.69 (dd, J =6.5, 1.8 Hz, 1H), 4.84 (d, J = 14.2 Hz, 1H), 4.28 (d, J = 14.1 Hz, 1H),4.10 (q, J = 7.2 Hz, 2H), 1.66 (d, J = 6.6 Hz, 3H), 1.32 (t, J = 7.2 Hz,3H) LCMS Method C; t_(R): 0.90 min; m/z: 406 [M + H] Example 164

3-ethyl-16-fluoro-11,19-dimethyl-20-oxa-3,4,10,11,23,25-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),9,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.80 (dd, J = 10.2, 2.7 Hz, 1H), 7.64 (s, 1H), 7.57 (s, 1H),7.28 (s, 1H), 7.24 (dd, J = 8.4, 2.8 Hz, 1H), 7.18 (dd, J = 8.5, 5.9 Hz,1H), 6.71 (s, 2H), 5.69- 5.63 (m, 1H), 4.08 (qd, J = 7.0, 3.3 Hz, 2H),3.50 (s, 3H), 3.35 (s, 1H), 2.75 (d, J = 14.9 Hz, 1H), 1.66 (d, J = 6.6Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H). LCMS Method C; t_(R): 1.41 min; m/z:420 [M + H] Example 165

11-ethyl-16-fluoro-3,19-dimethyl-20-oxa-3,4,10,11,23,25-hexaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),4,8(12),9,13,15,17,21(25),22-dccacn-22-amine 1H NMR (400 MHz,DMSO) δ 7.82-7.74 (m, 1H), 7.67 (s, 1H), 7.59 (s, 1H), 7.28 (s, 1H),7.28-7.12 (m, 2H), 6.70 (s, 2H), 5.62 (d, J = 4.7 Hz, 1H), 3.85-3.81 (m,2H), 3.79 (s, 3H), 3.66 (s, 1H), 2.76 (s, 1H), 1.64 (d, J = 6.6 Hz, 3H),1.22 (t, J = 7.1 Hz, 3H). LCMS Method C; t_(R): 1.40 min; m/z: 420 [M +H]

Example 166 (Method G)

-   -   Name:        {22-amino-3-ethyl-16-fluoro-20-oxa-3,4,8,11,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-1(24),2(6),4,9,11,13,15,17,21(25),22-decaen-19-yl}methanol    -   NMR: 1H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.67 (dd, J=10.3,        2.7 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.42 (dd, J=8.6, 5.8 Hz,        1H), 7.29-7.22 (m, 2H), 7.10 (d, J=1.2 Hz, 1H), 6.26 (s, 2H),        5.66 (d, J=1.6 Hz, 1H), 5.35 (d, J=6.5 Hz, 1H), 5.23 (t, J=6.0        Hz, 1H), 5.02 (d, J=14.7 Hz, 1H), 4.18 (d, J=14.6 Hz, 1H),        4.14-4.00 (m, 3H), 3.93-3.82 (m, 1H), 1.28 (t, J=7.2 Hz, 3H).    -   LCMS: Method D; t_(R): 2.18 min; m/z: 421 [M+H]

To a solution of3-[1-(2-{1-[(5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl]-1H-imidazol-2-yl}-5-fluorophenyl)-2-[(tert-butyldimethylsilyl)oxy]ethoxy]pyridin-2-amine(1.60 g, 2.60 mmol) in CH₃CN (20 mL) was added NBS (0.510 g, 2.86 mmol)at −20° C. After the addition, the mixture was stirred at −20° C. for 20min. The reaction mixture was poured into ice water and extracted withEtOAc. The organic layer was concentrated under reduced pressure and theresidue was purified by column chromatography on silica gel (0→100%EtOAc in PE) to give5-bromo-3-(1-(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)-2-(tert-butyldimethylsilyloxy)ethoxy)pyridin-2-amine(1.00 g, 55% yield) as a pale-yellow oil. LC/MS ESI (m/z): 693 [M+H]⁺.

To a solution of5-bromo-3-[1-(2-{1-[(5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl]-1H-imidazol-2-yl}-5-fluorophenyl)-2-[(tert-butyldimethylsilyl)oxy]ethoxy]pyridin-2-amine(760 mg, 1.09 mmol) in DMSO (8.0 mL) and MeOH (0.1 mL) was added CsF(832 mg, 5.41 mmol). The reaction mixture was stirred at r.t. for 1 hand then poured into ice water. The mixture was twice extracted withEtOAc and the combined extracts were concentrated under reducedpressure. The residue was purified by column chromatography (silica gel,0→3% MeOH in DCM) to give2-(2-amino-5-bromopyridin-3-yloxy)-2-(2-(1-((5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl)-1H-imidazol-2-yl)-5-fluorophenyl)ethanol(280 mg, 44% yield) as a white solid. LC/MS ESI (m/z): 579 [M+H]⁺.

To a solution of5-bromo-3-[i-(2-{1-[(5-bromo-1-ethyl-1H-pyrazol-4-yl)methyl]-1H-imidazol-2-yl}-5-fluorophenyl)-2-[(tert-butyldimethylsilyl)oxy]ethoxy]pyridin-2-amine(200 mg, 0.29 mmol) in MeOH (10.0 mL) was added bis(pinacolato)diboron(306 mg, 1.21 mmol), CsF (367 mg, 2.41 mmol) and H₂O (1.0 mL). Themixture was thrice degassed with N₂ before a solution of palladium(II)acetate (2 mg, 0.007 mmol) and cataCXium A (5 mg, 0.01 mmol) in toluene(0.5 mL) was added at 70° C. After the addition, the reaction mixturewas stirred at 70° C. under N₂ for 6 h. After concentration in vacuo,the reaction mixture was directly purified by reversed phase flashchromatography (C18, 2→95% MeCN in H₂O) followed by prep-TLC (5% MeOH inDCM) and then prep-HPLC (C18, 0→90% MeCN in H₂O+0.10% aq. NH₃) to givethe target product (6.1 mg, 3.0% yield) as a white solid. LC/MS ESI(m/z): 421 [M+H]⁺.

Example 167 (Method I)

-   -   Name:        22-amino-16-fluoro-11,19-dimethyl-20-oxa-4,6,10,11,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-1(24),2,4,8(12),9,13,15,17,21(25),22-decaene-3-carbonitrile    -   NMR: 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=1.8 Hz, 1H), 7.83 (s,        1H), 7.60 (s, 1H), 7.43 (dd, J=9.4, 2.6 Hz, 1H), 7.13 (td,        J=8.1, 2.6 Hz, 1H), 7.06 (dd, J=8.5, 5.6 Hz, 1H), 6.75 (d, J=1.6        Hz, 1H), 5.06 (t, J=10.1 Hz, 4H), 4.24 (d, J=16.0 Hz, 1H), 3.72        (s, 3H), 1.86 (d, J=6.3 Hz, 3H).    -   LCMS: Method B; t_(R): 1.86 min; m/z: 416 [M+H]

To a solution of1-((5-(4-fluoro-2-(1-(2-nitropyridin-3-yloxy)ethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-4-carbonitrile(32 mg, 0.070 mmol) in MeOH (2 mL) was added iron powder (20 mg, 0.36mmol), and sat. aq. NH₄Cl (2 mL). The reaction mixture was stirred at80° C. for 2 h, and then quenched with water and twice extracted withEtOAc. The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 50% EtOAc in PE) to afford1-((5-(2-(1-(2-aminopyridin-3-yloxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-4-carbonitrile(23 mg, 77% yield) as a yellow oil. LC/MS ESI (m/z): 418 [M+H]⁺.

To a solution of1-((5-(2-(1-(2-aminopyridin-3-yloxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-4-carbonitrile(40 mg, 0.09 mmol) in MeCN (2 mL) was added NBS (19 mg, 0.10 mmol) at 0°C. After stirring at r.t. overnight, the reaction was quenched withwater and then extracted with EtOAc twice. The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by preparative TLC (50% EtOAc in PE) to afford1-((5-(2-(1-(2-amino-5-bromopyridin-3-yloxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-4-carbonitrile(32 mg, 67% yield) as a white solid. LC/MS ESI (m/z): 496 [M+H]⁺.

To a suspension of1-((5-(2-(1-(2-amino-5-bromopyridin-3-yloxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-4-carbonitrile(32 mg, 0.060 mmol) in 2-methyl-2-butanol (2 mL) was added Pd(OAc)₂ (3.6mg, 0.016 mmol), cataCXium A (12 mg, 0.030 mmol) and KOAc (24 mg, 0.24mmol) at 25° C. The mixture was thrice degassed with N₂ and then stirredat 120° C. for 5 h. The reaction was directly concentrated in vacuo, andthe residue was purified by preparative TLC (5% MeOH in DCM) followed byprep-HPLC (Gemini 5 um C18 250*21.2 mm, MeCN in H₂O+0.1% FA) to give thetarget product (2.0 mg, 5.9% yield) as a white solid. LC/MS ESI (m/z):416 [M+H]⁺.

Example 168 (Method J)

-   -   Name:        22-amino-16-fluoro-11,19-dimethyl-20-oxa-4,5,10,11,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-1(24),2,5,8(12),9,13,15,17,21(25),22-decaene-3-carbonitrile    -   NMR: 1H NMR (400 MHz, DMSO) δ 7.77 (dd, J=10.2, 2.5 Hz, 1H),        7.55 (d, J=1.8 Hz, 1H), 7.44 (s, 1H), 7.34-7.23 (m, 2H), 6.48        (d, J=1.7 Hz, 1H), 6.05 (s, 2H), 5.04-4.93 (m, 1H), 3.90 (d,        J=15.8 Hz, 1H), 3.63 (s, 3H), 2.97 (d, J=15.7 Hz, 1H), 1.80 (d,        J=6.2 Hz, 3H).    -   LCMS: Method C; t_(R): 0.46 min; m/z: 416 [M+H]

To a solution of22-amino-16-fluoro-11,19-dimethyl-4-{[2-(trimethylsilyl)ethoxy]methyl}-20-oxa-4,5,10,11,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-1(24),2,5,8(12),9,13,15,17,21(25),22-decaene-3-carbonitrile(50 mg, 0.09 mmol) in DCM (8 mL) was added TFA (105 mg, 0.92 mmol).After the addition, the mixture was stirred at r.t. for 12 h. Themixture was concentrated under reduced pressure, and the residue waspurified by prep-HPLC (Gemini 5 μm C18 250*21.2 mm; MeCN in H₂O+0.1% FA)to give the target product as a white solid (13 mg, yield: 34%). LC-MS(ESI): m/z 416 [M+H]⁺.

Example 169 (Method K)

-   -   Name:        (19R)-22-amino-16-fluoro-4,19-dimethyl-20-oxa-4,5,11,12,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-1(24),2,5,8,10,13,15,17,21(25),22-decaene-3-carbonitrile    -   NMR: 1H NMR (400 MHz, DMSO-d6) δ 7.79-7.73 (m, 2H), 7.54 (d,        J=1.8 Hz, 1H), 7.49 (dd, J=8.8, 5.2 Hz, 1H), 7.32 (td, J=8.3,        2.9 Hz, 1H), 6.25 (d, J=1.3 Hz, 1H), 6.17 (s, 2H), 5.99 (d,        J=1.9 Hz, 1H), 5.11 (q, J=6.2, 5.4 Hz, 1H), 4.20 (d, J=16.0 Hz,        1H), 4.03 (s, 3H), 3.23 (d, J=16.1 Hz, 1H), 1.73 (d, J=6.2 Hz,        3H).    -   LCMS: Method F; t_(R): 0.83 min; m/z: 416 [M+H].

To a solution of5-bromo-3-(1-(2-(5-((1-ethyl-1H-pyrazol-4-yl)methyl)-3-fluoro-1H-pyrazol-1-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine(70 mg, 0.13 mmol) in EtOH (2 mL) and H₂O (0.5 mL), was added NH₄Cl (69mg, 1.3 mmol) and iron powder (36 mg, 0.64 mmol). The reaction wasstirred at 75° C. for 1 h, and then concentrated in vacuo. The residuewas purified by prep-TLC (5% MeOH in DCM) to give3-((1-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazol-5-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile(64 mg, 97%) as a brown solid. LC/MS ESI (m/z): 512 [M+H]⁺.

To a solution of3-((1-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazol-5-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile(64 mg, 0.12 mmol) in trifluoroacetic acid (3 mL), was addedtriethylsilane (0.40 mL, 2.5 mmol). The reaction was stirred at 50° C.for 6 h. The mixture was cooled to r.t. and concentrated in vacuo. Theresidue was diluted with EA (10 mL) and neutralized with sat. aq.NaHCO₃. The layers were separated, and the aq. layer was extracted withEA (3×10 mL). The combined organic phases were washed with brine (5 mL),dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by prep-TLC (5% MeOH in DCM) to give3-((1-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile(35 mg, 56%) as a white gum. LC/MS ESI (m/z): 496 [M+H]⁺.

To a mixture of3-((1-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole-5-carbonitrile(35 mg, 0.071 mmol), Pd(OAc)₂ (3 mg, 0.014 mmol) and cataCXium A (8 mg,0.02 mmol) in 2-methyl-2-butanol (3.5 mL), was added potassium acetate(35 mg, 0.35 mmol). The resulting mixture was thrice degassed with N₂,and then stirred at 120° C. overnight. The mixture was cooled to r.t.,filtered, and concentrated in vacuo. The residue was purified byprep-TLC (5% MeOH in DCM), followed by prep-HPLC (Gemini 5 um C18250*21.2 mm, MeCN in H₂O+0.1% FA), and finally by chiral SFC (ChiralCelOJ-H 4.6*250 mm, 40% MeOH+0.05% DEA in CO₂ over 8.0 min) to obtain thetarget eutomer (t_(R) 4.0 min, 5.0 mg, 17%) as a white solid (LC/MS ESI(m/z): 416 [M+H]⁺.

Example 170 (Method L)

-   -   Name:        3-ethyl-17-fluoro-5-methyl-21-oxa-4,5,12,24-tetraazapentacyclo[20.3.1.0^(2,6).0^(8,13).0^(14,19)]hexacosa-1(25),2(6),3,8(13),9,11,14,16,18,22(26),23-undecaen-23-amine    -   NMR: 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=3.4 Hz, 1H), 7.66-7.59        (m, 2H), 7.48 (dd, J=8.0, 4.7 Hz, 1H), 7.37-7.32 (m, 2H), 7.24        (td, J=8.5, 2.7 Hz, 1H), 5.96 (d, J=1.7 Hz, 1H), 5.77 (s, 2H),        5.18 (d, J=13.4 Hz, 1H), 4.71 (d, J=14.7 Hz, 1H), 4.25 (d,        J=16.6 Hz, 1H), 4.02 (s, 3H), 3.29 (s, 1H), 2.58 (qd, J=7.5, 1.8        Hz, 2H), 1.11 (t, J=7.5 Hz, 3H).    -   LCMS: Method G; t_(R): 2.07 min; m/z: 416 [M+H]

To a solution of5-bromo-3-((2-(3-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)-5-fluorobenzyl)oxy)-2-nitropyridine(185 mg, 0.342 mmol) in EtOH (5 mL) and H₂O (1 mL), was added ironpowder (191 mg, 3.42 mmol), and NH₄Cl (366 mg, 6.85 mmol). The mixturewas stirred at 80° C. for 3 h, then poured into water (80 mL) andextracted with EtOAc (80 mL×3). The combined organic layers were washedwith sat. aq. NaCl (60 mL×2), dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (10→50% EtOAc in PE) to give5-bromo-3-((2-(3-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)-5-fluorobenzyl)oxy)pyridin-2-amine(165 mg, 94%) as a white solid. LC/MS (ESI): m/z=496 [M+H]⁺.

To a solution of5-bromo-3-((2-(3-((3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)-5-fluorobenzyl)oxy)pyridin-2-amine(150 mg, 0.294 mmol) in DMF (5 mL), was added NBS (52 mg, 0.29 mmol).The reaction was stirred at r.t. for 3 h, then poured into water (80 mL)and extracted with EA (80 mL×3). The combined organic layers were washedwith sat. NaCl (60 mL×2), dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (10→50% EtOAc in PE) to give5-bromo-3-((2-(3-((4-bromo-3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)-5-fluorobenzyl)oxy)pyridin-2-amine(90 mg, 52%) as a white solid. LC/MS (ESI): m/z=574 [M+H]⁺.

To a solution of5-bromo-3-((2-(3-((4-bromo-3-ethyl-1-methyl-1H-pyrazol-5-yl)methyl)pyridin-2-yl)-5-fluorobenzyl)oxy)pyridin-2-amine(80 mg, 0.14 mmol) in MeOH (8 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (103 mg,0.410 mmol), Pd(OAc)₂ (7.3 mg, 0.033 mmol), cataCXium A (23 mg, 0.065mmol), and aq. CsF (2 M, 0.20 mL, 0.40 mmol). The reaction was stirredat 80° C. for 5 h, then poured into water (80 mL) and extracted withEtOAc (80 mL×3). The combined organic layers were washed with sat. NaCl(60 mL×2), dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by column chromatography on silica gel(50% EtOAc in PE) followed by prep-HPLC (Xbridge C18 OBD 250*19 mm 5urn, MeCN in 1H₂O+0.1% FA) to give the target product (1.9 mg, 3.3%) asa white solid. LC/MS (ESI): m/z=416 [M+H]⁺.

The following compounds were prepared in a similar manner:

Example 171

(19R)-3-ethyl-16-fluoro-5,10,19-trimethyl-20-oxa- 4,5,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.78 (s, 1H), 7.67 (d, J = 9.9 Hz, 1H), 7.30 (d, J = 1.7 Hz,1H), 7.19-7.15 (m, 2H), 6.20 (s, 1H), 5.71 (s, 2H), 5.29-5.17 (m, 1H),3.95 (s, 3H), 3.87 (s, 3H), 3.85-3.80 (m, 1H), 2.93 (d, J = 16.2 Hz,1H), 2.49-2.46 (m, 2H), 1.69 (d, J = 6.3 Hz, 3H), 1.07 (t, J = 7.5 Hz,3H). LCMS Method F; t_(R): 0.82 min; m/z: 433 [M + H] Example 172

(19R)-3-(2,2-difluoroethyl)-16-fluoro-5,10,19-trimethyl-20-oxa-4,5,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.80 (s, 1H), 7.68 (d, J = 10.3 Hz, 1H), 7.34 (d, J = 1.7 Hz,1H), 7.21-7.14 (m, 2H), 6.20 (tt, J = 4, 56 Hz, 1H), 6.20 (s, 1H), 5.78(s, 2H), 5.33-5.19 (m, 1H), 4.00 (s, 3H), 3.87 (m, 4H), 3.14- 3.05 (m,2H), 2.95 (d, J = 16.2 Hz, 1H), 1.70 (d, J = 6.2 Hz, 3H). LCMS Method H;t_(R): 0.91 min; m/z: 469 [M + H] Example 173

(19R)-3-ethyl-16-fluoro-5,10,19-trimethyl-20-oxa-9-thia- 4,5,11,23-tetraazapentacyclo[19.3.1,0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8(12),10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400MHz, Chloroform-d) δ 7.50 (d, J = 1.8 Hz, 1H), 7.33 (dd, J = 9.7, 2.7Hz, 1H), 7.12 (dd, J = 8.4, 5.6 Hz, 1H), 7.01 (td, J = 8.2, 2.7 Hz, 1H),6.47 (d, J = 1.8 Hz, 1H), 5.21-5.13 (m, 1H), 4.83 (s, 2H), 4.00 (s, 3H),3.92 (d, J = 16.3 Hz, 1H), 3.72 (d, J = 16.3 Hz, 1H), 2.72 (s, 3H), 2.65(p, J = 7.6 Hz, 2H), 1.79 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 7.6 Hz, 3H).LCMS Method H; t_(R): 0.99 min; m/z: 491 [M + H + MeCN] Example 174

(19R)-3-cyclobutyl-16-fluoro-4,19-dimethyl-20-oxa- 4,5,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸lpentacosa-1(24),2,5,8,10,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO-d6) δ 7.83 (dd, J = 9.8, 3.0 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H),7.40 (dd, J = 8.8, 5.2 Hz, 1H), 7.26 (td, J = 8.3, 3.0 Hz, 1H), 7.20 (d,J = 1.7 Hz, 1H), 6.20 (d, J = 1.9 Hz, 1H), 6.00 (d, J = 1.9 Hz, 1H),5.89 (br s, 2H), 5.24-5.16 (m, 1H), 3.90 (d, J = 15.7 Hz, 1H), 3.77 (s,3H), 3.77-3.68 (m, 1H), 3.00 (d, J = 15.6 Hz, 1H), 2.33-2.23 (m, 1H),2.20-2.09 (m, 2H), 2.00- 1.84 (m, 2H), 1.71 (d, J = 6.2 Hz, 3H),1.71-1.59 (m, 1H). LCMS Method F; t_(R): 0.90 min; m/z: 445 [M + H]Example 175

3-ethyl-16-fluoro-5,10-dimethyl-20-oxa-9-thia-4,5,11,23-tetraazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8(12),10,13,15,17,21(25),22-decaen-22- amine 1H NMR (400MHz, DMSO) δ 7.65 (dd, J = 9.8, 2.2 Hz, 1H), 7.34 (d, J = 1.7 Hz, 1H),7.31-7.17 (m, 2H), 6.25 (d, J = 1.6 Hz, 1H), 5.77 (s, 2H), 5.16 (d, J =13.2 Hz, 1H), 4.83 (d, J = 14.4 Hz, 1H), 4.25 (d, J = 16.3 Hz, 1H), 3.94(s, 3H), 3.52-3.39 (m, 1H), 2.66 (s, 3H), 2.57-2.42 (m, 2H), 1.09 (t, J= 7.5 Hz, 3H). LCMS Method K; t_(R): 0.87 min; m/z: 436 [M + H] Example176

3-ethyl-16-fluoro-5,10-dimethyl-20-oxa-4,5,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.76 (s, 1H), 7.63 (d, J = 9.4 Hz, 1H), 7.32 (d, J = 1.7 Hz,1H), 7.24-7.17 (m, 2H), 6.22 (d, J = 1.6 Hz, 1H), 5.72 (s, 2H), 5.10 (d,J = 13.3 Hz, 1H), 4.96 (d, J = 14.1 Hz, 1H), 3.96 (s, 3H), 3.89-3.80 (m,4H), 2.97 (d, J = 16.1 Hz, 1H), 2.56-2.52 (m, 2H), 1.09 (t, J = 7.5 Hz,3H). LCMS Method F; t_(R): 0.28 min; m/z: 419 [M + H] Example 177

(19R)-3-(cyclopropylmethyl)-16-fluoro-4,19-dimethyl-20-oxa-4,5,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸lpentacosa-1(24),2,5,8,10,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz, DMSO)δ 7.81 (dd, J = 9.8, 2.9 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.42 (dd, J= 8.7, 5.2 Hz, 1H), 7.33 (d, J = 1.7 Hz, 1H), 7.30-7.23 (m, 1H), 6.23(d, J = 1.0 Hz, 1H),5.95 (d, J = 1.4 Hz, 1H), 5.81 (s, 2H), 5.18- 5.09(m, 1H), 3.95 (d, J = 15.9 Hz, 1H), 3.83 (s, 3H), 3.08 (d, J = 15.7 Hz,1H), 2.62 (d, J = 6.5 Hz, 2H), 1.71 (d, J = 6.2 Hz, 3H), 0.90-0.81 (m,1H), 0.45-0.32 (m, 2H), 0.16-0.07 (m, 1H), 0.05-−0.06 (m, 1H). LCMSMethod F; t_(R): 0.97 min; m/z: 445 [M + H] Example 178

(19R)-3-(cyclopropylmethyl)-16-fluoro-5,10,19-trimethyl-20-oxa-4,5,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2(6),3,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.81 (s, 1H), 7.71-7.61 (m, 1H), 7.31 (d, J = 1.7 Hz, 1H), 7.18(dd, J = 8.0, 1.6 Hz, 2H), 6.24 (d, J = 1.5 Hz, 1H), 5.99 (s, 2H), 5.27(d, J = 4.6 Hz, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.84 (d, J = 16.5 Hz,1H), 2.94 (d, J = 16.1 Hz, 1H), 2.42 (d, J = 6.5 Hz, 2H), 1.70 (d, J =6.3 Hz, 3H), 0.97-0.79 (m, 1H), 0.43-0.24 (m, 2H), 0.17-0.02 (m, 1H),0.01-−0.10 (m, 1H). LCMS Method K; t_(R): 0.56 min; m/z: 459 [M + H]Example 179

(19R)-3-(cyclopropylmethyl)-16-fluoro-4,10,19-trimethyl-20-oxa-4,5,10,11,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸]pentacosa-1(24),2,5,8,11,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz, DMSO)δ 7.66 (dd, J = 10.3, 2.1 Hz, 1H), 7.55 (s, 1H), 7.27 (d, J = 1.7 Hz,1H), 7.18-7.10 (m, 2H), 6.23 (s, 1H), 5.70 (s, 2H), 5.31-5.24 (m, 1H),3.85 (s, 3H), 3.78 (s, 3H), 3.65 (d, J = 14.9 Hz, 1H), 2.85 (d, J = 15.0Hz, 1H), 2.58-2.52 (m, 2H), 1.69 (d, J = 6.3 Hz, 3H), 0.87-0.75 (m, 1H),0.43-0.30 (m, 2H), 0.15-0.06 (m, 1H), 0.03-−0.05 (m, 1H). LCMS Method F;t_(R): 0.74 min; m/z: 459 [M + H] Example 180

(19R)-3-(2,2-difluoroethyl)-10-(difluoromethyl)-16-fluoro-5,19-dimethyl-20-oxa-4,5,11,12,23-pentaazapentacyclo[19.3.1.0²,⁶.0⁸,¹².0¹³,¹⁸lpentacosa-1(24),2(6),3,8,10,13,15,17,21(25),22-decaen-22-amine 1H NMR (400 MHz,DMSO) δ 7.87 (dd, J = 9.8, 2.9 Hz, 1H), 7.49 (dd, J = 8.8, 5.2 Hz, 1H),7.41 (d, J = 1.7 Hz, 1H), 7.35 (td, J = 8.3, 3.0 Hz, 1H), 7.05 (t, J =54.5 Hz, 1H), 6.65 (s, 1H), 6.16 (dt, J = 56.3, 4.7 Hz, 1H), 5.93 (s,3H), 5.12-5.00 (m, 1H), 4.32 (d, J = 17.1 Hz, 1H), 4.02 (s, 3H),3.21-3.14 (m, 2H), 3.10 (dd, J = 16.5, 4.6 Hz, 1H), 1.71 (d, J = 6.2 Hz,3H). LCMS Method F; t_(R): 1.05 min; m/z: 505 [M + H]

Example 181 (Method M)

-   -   Name:        (19R)-3-ethyl-16-fluoro-5-methoxy-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine    -   NMR: 1H NMR (400 MHz, DMSO) δ 7.80-7.60 (m, 1H), 7.51 (s, 1H),        7.41 (d, J=1.8 Hz, 1H), 7.14 (dd, J=7.7, 1.7 Hz, 2H), 6.27 (d,        J=1.6 Hz, 1H), 6.11 (s, 2H), 5.37-5.21 (m, 1H), 3.92 (s, 3H),        3.91-3.82 (m, 5H), 3.46 (s, 1H), 2.56 (s, 1H), 1.70 (d, J=6.2        Hz, 3H), 1.23 (t, J=7.1 Hz, 3H).    -   LCMS: Method F; t_(R): 0.79 min; m/z: 449 [M+H]

A mixture of(19R)-5-(benzyloxy)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine(30 mg, 0.060 mmol) and Pd/C (30 mg, 10% wt.) in anhydrous MeOH (2 mL)was stirred at 25° C. for 1.5 h under a balloon of H₂. The reaction wasfiltered through celite and the filtrate was concentrated in vacuo. Theresidue was purified by prep-HPLC (Shim-pack GIST C18 250*20 mm; MeCN inH₂O+0.1% FA) to give(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-1(24),2(6),8,11,13,15,17,21(25),22-nonaen-5-one(9.8 mg, 39% yield) as a white solid. LC/MS (ESI) m/z: 435.2 [M+H]⁺.

To a solution of(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0^(2,6).0^(8,12).0^(13,18)]pentacosa-1(24),2(6),8,11,13,15,17,21(25),22-nonaen-5-one(64 mg, 0.15 mmol), and K₂CO₃ (40 mg, 0.29 mmol) in anhydrous DMF (1.5mL) was added iodomethane (0.010 mL, 0.16 mmol) dropwise at 0° C. Thereaction was stirred at 25° C. for 2 h. The reaction mixture wasfiltered, and the filtrate was partitioned between EtOAc and water. Thelayers were separated, and the aq. phase was extracted with EA (30 mL).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified byprep-HPLC (Column: YMC-Actus Triart C18 250*21 mm; H₂O+0.1% FA) to givethe target product (20 mg, 310% yield) as a white solid. LC/MS (ESI)m/z: 449 [M+H]⁺.

Inhibition Assays Example 182 Biochemical Kinase Assay

First, 250 nL of compound dissolved in DMSO (100-fold of the desiredconcentration) was dispensed into a 384-well plate. A 12.5 μL substratesolution containing ATP (2 mM) and fluorogenic phosphorylation substrateAQTO101 (26 μM for ALK and ROS1, AssayQuant) or AQT0104 (26 μM for TRKA,AssayQuant) in buffer (50 mM HEPES pH 7.5, 0.01% Brij-35, 0.5 mM EGTA,10 mM MgCl₂) was added and mixed thoroughly. Then, a 12.5 μL kinasesolution containing ALK-wt (1.5 nM, Carna, 08-518), ALK ALKL1196M/G1202R (3 nM, SignalChem, A19-12NG), ROS1-wt (0.6 nM, Carna,08-163), ROS1-G2032R (0.5 nM, SignalChem, R14-12BG), or TRKA-wt (1 nM,BPS Bio, 40280) kinase domains in buffer (50 nM HEPES pH 7.5, 0.01%Brij-35, 2% glycerol, 0.4 mg/mL BSA, 0.5 mM EGTA, and 10 mM MgCl₂) wasadded and mixed thoroughly. The plate was sealed and read by SpectraMaxParadigm at λ=485 nm every 2 minutes for 120 minutes at 30° C. Exemplarydata is given in Table 3. Initial rates of reaction (v) were calculatedfrom the change in fluorescence intensity over time during the initial,linear portion of the reaction. Finally, apparent inhibitory constants(K_(i) ^(app)) were determined from regression of v and I (inhibitorconcentration) to Morrison Equation (E=enzyme concentration):

$v = {1 - \frac{\left( {E + I + K_{i}^{app}} \right) - \sqrt{\left( {E + I + K_{i}^{app}} \right)^{2} - {4{EI}}}}{2E}}$

Exemplary data is given in Table 3 (nd=not determined).

TABLE 3 Biochemical Assay Activity Summary: ALK- L1196M- ROS1- ExampleG1202R ALK-wt G2032R ROS1-wt TRKA-wt 1 A A A A A 2 B A A A B 3 A A A A A4 A A A A A 5 A A A A C 6 A A A A B 9 A A A A C 10 A A A A C 11 B A A AC 12 A A A A C 13 A A A A C 14 A A A A B 15 A A A A C 16 A A A A B 17 BA B A B 18 A A A A C 19 A A A A A 20 A A A A B 22 A A A A C 24 A A B A C25 B A B A C 26 A A A A B 27 A A A A C 28 A A A A A 29 A A A A B 30 A AB A C 31 A A A A A 32 A A A A B 33 A A A A A 34 A A B A C 35 A A A A B36 A A A A B 37 A A A A B 38 B A A A C 39 B A A A C 40 B A A A C 41 A AA A C 42 A A A A B 44 B A A A B 45 A A A A A 46 A A A nd A 47 B A A A B48 A A A A C 49 B A B A C 50 A A A A A 52 A A A A B 53 A A A A B 54 A AA A C 55 A A A A B 58 A A A A C 59 C A B A B 60 B A B A C 61 C B C B C62 A A B A C 63 A A A A C 64 A A A A C 65 A A A A C 67 A A A A B 68 A AA A B 69 A A A A B 70 A A A A B 71 A A A A A 72 A A A A B 73 A A A A B74 A A A A A 75 A A A A B 76 A A A A A 77 A A A A B 78 A A A A B 79 A AA A C 80 A A A A A 81 A A A A B 82 A A A A B 83 A A A A C 84 A A A A C85 A A A A C 86 B A A A C 87 A A A A A 88 A A A A B 89 A A A A C 90 A AA A B 91 A A A A B 92 A A A A C 93 A A A A B 94 A A A A B 98 A A A A A99 A A A A B 100 A A A A B 102 A A A A A 103 A A A A B 104 A A A A C 105A A A A C 106 A A A A B 107 A A A A B 108 A A A A B 109 A A A A A 110 AA A A C 111 A A A A B 112 A A A A B 114 A A A A B 116 A A A A B 117 A AB A C 118 B A C A A 119 A A B A A 120 B A B A B 121 A A A A B 122 A A AA B 123 A A A A C 124 A A A A B 126 A A A A C 128 A A A A B 130 A A A AB 132 A A A A B 133 A A B A C 134 A A A A B 135 A A A A B 137 A A A A B138 A A A A C 139 A A A A B 140 A A A A B 141 A A A A B 143 A A A A B144 A A A A B 145 A A A A B 146 A A A A B 147 A A A A A 148 A A B A C149 A A A A A 150 A A A A B 151 A A A A A 152 A A A A A 153 A A A A A154 A A A A C 155 A A A A A 156 A A A A B 157 A A A A A 158 A A A A A159 A A nd nd C 160 A A A A C 162 A A A A A 163 A A A A B 164 B A A A C165 B A B A B 166 B A B A C 167 B A B A C 168 A A A A C 169 A A A A A171 A A A A A 173 A nd nd nd A 174 A A A A B 175 A A A A B 176 A A B A C177 A A A A B 178 A A A A B 179 A A A A B 180 A A A A B 181 A A A A B

Compound potency can be interpreted by binning K_(i) ^(app) valuesagainst the targets: bin A for high potency, K_(i) ^(app)<50 nM; bin Bfor medium potency, 50 nM≤K_(i) ^(app)≤500 nM; and bin C for lowpotency, K_(i) ^(app)>500 nM. Compounds are more desirable if theyexhibit smaller K_(i) ^(app) values against the on-target kinases (ROS1or ALK) and larger K_(i) ^(app) values against the off-target kinase(TRKA). Compounds that potently inhibit the on-target kinases (ROS1 orALK) are also expected to inhibit ROS1 or ALK oncoproteins that areexpressed in human cancers, providing support for the potential clinicalefficacy of such compounds. Similarly, compounds that do not potentlyinhibit the off-target kinase (TRKA) are expected to poorly inhibitTRK-family kinases in humans and hence avoid potential clinical toxicityarising from TRKA, TRKB, or TRKC inhibition.

Example 183 Generation of Ba/F3 Stable Cell Lines

Genes encoding CD74-ROS1 wild-type (wt), CD74-ROS1 G2032R, CD74-ROS1S1986F, CD74-ROS1 L2026M, CD74-ROS1 D2033N, EML4-ALK wt (variant 1),EML4-ALK G1202R (variant 1), EML4-ALK L1196M/G1202R (variant 1),EML4-ALK G1202R/G1269A (variant 1), EML4-ALK G1202R/L1198F (variant 1),and TPM3-TRKA were synthesized at GeneRay, cloned into the retroviralconstruct pMSCV-puro (Biovector), and packaged into retroviralparticles. The virus was used to infect Ba/F3 cells (RIKEN) atmultiplicity of infection=1 for 1 day. Infected cells were rescued inmedia (RPMI-1640 with 10% fetal bovine serum and 1% streptomycin andpenicillin) supplemented with mouse IL-3 (10 ng/mL) for 2 days, andstable cell lines were selected by IL-3 withdrawal and puromycin (0.8μg/mL) for 7 days. Monoclones were selected by single-cell dilution inIL-3-free medium containing puromycin (0.8 μg/mL). Transformation ofdesired genes was confirmed by Sanger sequencing and western blot usingthe following antibodies: ROS1 (CST #3287), ALK (CST #3633), and pan-TRK(Abcam #76291).

Cell Proliferation Assay

Stable cells were plated at 1,000 cells/well (40 μL) in a 384-well platefor 1 day. Test compounds (40 nL) were then added in a 3-fold dilutionseries using the TECAN EV0200 liquid handler and incubated for 72 hours.Plates were equilibrated at room temperature for 15 minutes followed byaddition of 40 μL CellTiter-Glo reagent (Promega). Luminescence wasmeasured on a plate reader. Half-maximal inhibitory concentration (IC₅₀)was calculated from percent inhibition and inhibitor concentration usingfour-parameter logistic regression. Compound potency can be interpretedby binning IC₅₀ values: bin A for high potency, 0.1 nM≤IC₅₀≤50 nM; bin Bfor medium potency, 50 nM≤IC₅₀≤500 nM; and bin C for low potency,IC₅₀>500 nM. Compounds are more desirable if they exhibit smaller IC₅₀values against the on-target Ba/F3 cells (ROS1- or ALK-fusion) andlarger IC₅₀ values against the off-target Ba/F3 cells (TRKA-fusion).Exemplary data is given in Table 4 (nd is not determined).

TABLE 4 Cell Assay Activity Summary: CD74- EML4-ALK- ROS1- CD74- L1196M-TPM3- EML4- Example G2032R ROS1-wt G1202R NTRK1-wt ALK-wt 1 A A A B A 2A A C B A 3 A nd A B A 4 A A B B A 5 A A A C A 6 A A B B A 7 B nd B C nd8 A A A B A 9 A A B C A 10 A C B C A 11 A A B C A 12 A A A C A 13 A A AC A 14 A A B C A 15 A A B C A 16 A A B B A 17 A A C B A 18 A A A C A 19A A A B A 20 A A A B A 21 A A A B A 22 A A A C A 23 A A A B A 24 A A B CA 25 A A B C A 26 A A A B A 27 A A B C A 28 A A A B A 29 A A A C A 30 AA B C A 31 A A A B A 32 A A B B A 33 A A A B A 34 A A B C A 35 A A A B A36 A A A B A 37 A A A C A 38 A A C C B 39 B A C C A 40 A A B C A 41 A AA B A 42 A A A B A 43 A A A B A 44 A A B C A 45 A A A B A 46 A A A B A47 A A B B A 48 A A B C A 49 A A A C A 50 A A A B A 51 C C C C C 52 A AA B A 53 A A A B A 54 A A A C A 55 A A A B A 56 C C C C C 58 A A B C A59 B A C B nd 61 B A C C B 62 A A B B A 63 A A B C A 64 A A B C A 65 A AB C A 67 A A B B A 68 A A B B A 69 A A A B A 70 A A B B A 71 A A A A A72 A A A B A 73 A A A B A 74 A A A A A 75 A A A B A 76 A A A B A 77 A AA B A 78 A A A B A 79 A A A C A 80 A A A B A 81 A A A B A 82 A A A B A83 A A A C A 84 A A B C A 85 A A B C A 86 A A C B A 87 A A A A A 88 A AA B A 89 B A B C A 90 A A A B A 91 A A A B A 92 A A B B A 93 A A B B A94 A A A B A 95 A A A B A 96 A A B B A 97 A A A B A 98 A A A A A 99 A AA B A 100 A A A B A 101 A A B C A 102 A A A A A 103 A A A B A 104 A A BB A 105 A A B C A 106 A A A B A 107 A A B B A 108 A A A B A 109 A A A BA 110 A A A C A 111 A A B B A 112 A A B B A 113 B B C C A 114 A A A C A115 A A B C A 116 A A A B A 117 A A B C A 118 B A B B A 119 A A B A A120 B A C C B 121 A A A B A 122 A A A B A 123 B A C C A 124 A A A B A125 A A A C A 126 A A A C A 127 A A A C A 128 A A A B A 129 A A B C B130 A A A B A 131 C B C C B 132 A A B B A 133 A A A C A 134 A A A B A135 A A A B A 136 A A B C B 137 A A A B A 138 A A A C A 139 A A A B A140 A A A B A 141 A A A B A 142 A nd A B nd 143 A A A B A 144 A A A B A145 A A B B A 146 A A A B A 147 A A B B A 148 nd nd nd C nd 149 A A B AA 150 A A B B A 151 A A A B A 152 A A A B A 153 nd nd nd C nd 154 A A BC A 155 A A C B A 156 nd nd A B nd 157 A A A B A 158 A A A B A 159 A A BC A 160 A A A C A 161 A A A A A 162 A A A B A 163 A A B B A 164 A nd B CB 165 A A C B B 168 A A B C A 169 A A B B A 170 A A A B A 171 A A A B A172 A A A B A 173 A A A A A 174 A A B B A 175 A A A B A 176 A A B C A177 A A A B A 178 A A A B A 179 A A A B A 180 A A B C A 181 A A A B A

Potencies of the compounds provided herein were compared to commerciallyavailable ALK inhibitors (tested in the same assays) to assess relativepotencies across ALK mutations. Exemplary data of one compound ofFormula (I) and several ALK inhibitors are given in Table 5.

TABLE 5 Cell Potency Compared to Reference Compounds: Cell with Onecompound ALK fusion of Formula (I) Crizotinib Ceritinib AlectinibBrigatinib Lorlatinib Wild-type A C B B B A G1202R A D D D C BG1202R/L1196M A D D D D D G1202R/G1269A A D C D C D G1202R/L1198F A C DD C D A: ≤10 nM B: >10 nM and ≤100 nM C: >100 nM and ≤500 nM D: >500 nMand <4000 nM

Ba/F3 proliferation is driven by the transduced oncogenes in the sameway that cancer cell proliferation in humans is driven by the expressionof equivalent oncogenes. Hence, compounds that potently inhibit theproliferation of the on-target Ba/F3 cells (ROS1- or ALK-fusion) arealso expected to inhibit human cancers that express equivalentoncogenes, providing support for the potential clinical efficacy of suchcompounds. Similarly, compounds that do not potently inhibit theoff-target Ba/F3 cells (TRKA-fusion) are expected to poorly inhibitTRK-family kinases in humans and hence avoid the clinical toxicityarising from TRKA, TRKB, or TRKC inhibition.

TRKA selectivity was calculated by dividing a compound's TRKA potency byits primary target potency (e.g. TPM3-NTRK1-wt IC₅₀/CD74-ROS1-wt IC₅₀).Compound selectivity can be interpreted by binning ratio values: bin Afor very high selectivity, ratio >30-fold; bin B for high selectivity,ratio >10-fold; bin C for moderate selectivity, ratio ≥1; and bin D forlow selectivity, ratio <1. Compounds are more desirable if they exhibithigher selectivity ratios. Exemplary data are given in Table 6. (nd=notdetermined).

TABLE 6 Cell Assay Selectivity Summary: TPM3-NTRK1- TPM3-NTRK1-TPM3-NTRK1- TPM3-NTRK1- wt/CD74- wt/CD74- wt/EML4-ALK- wt/EML4- ExampleROS1-G2032R ROS1-wt L1196M-G1202R ALK-wt 1 A A A A 2 B A D B 3 A nd B A4 B A D C 5 A A A A 6 A A C A 7 A nd A nd 8 A A B A 9 B A C A 10 A D C A11 A A C A 12 A A A A 13 A A A A 14 B A C A 15 A A B A 16 B A C B 17 B AD B 18 A A A A 19 A A C A 20 A A B A 21 A A B A 22 A A A A 23 A A C A 24A A C A 25 A A B A 26 A A B A 27 A A A A 28 A A C A 29 A A A A 30 A A CA 31 A A C A 32 A A C B 33 A A B A 34 A A B A 35 A A C A 36 A A C A 37 AA A A 38 A A C B 39 A A C A 40 A A A A 41 A A B A 42 A A B A 43 A A C B44 A A C A 45 A A B A 46 A A C A 47 A A C B 48 A A B A 49 A A B A 50 A AB A 51 C C C D 52 A A C B 53 A A A A 54 A A B A 55 A A C A 56 D D D D 58A A B A 59 C A D nd 61 A A B A 62 B A C A 63 A A B A 64 A A B A 65 A A BA 67 A A C A 68 B A C B 69 A A B A 70 A A C A 71 A B C B 72 A A C A 73 AA B A 74 A A B A 75 A A C A 76 A A B A 77 A A C A 78 A A B A 79 A A A A80 A A B A 81 A A B A 82 A A B A 83 A A A A 84 A A C A 85 A A C A 86 B AD C 87 A A C A 88 B A C A 89 A A B A 90 A A C A 91 A A A A 92 A A C C 93A A C B 94 A A A A 95 A A C A 96 A A C A 97 A A B A 98 A A C B 99 A A CB 100 A A A A 101 A A A A 102 A A C B 103 A A B A 104 A A C A 105 A A BA 106 A A B A 107 A A C C 108 A A B A 109 A A A A 110 A A A A 111 B A CA 112 C A D A 113 A A C A 114 A A A A 115 A A B A 116 A A A A 117 A A BA 118 D A D A 119 D A D A 120 C A D C 121 A A A A 122 A A C B 123 C A CA 124 A A A A 125 A A A A 126 A A A A 127 A A A A 128 A A C B 129 A A AA 130 A A B A 131 B A C B 132 A A C A 133 A A A A 134 A A A A 135 A A AA 136 A A A A 137 A A A A 138 A A A A 139 A A C A 140 A A A A 141 A A AA 142 A nd B nd 143 A A B A 144 A A B A 145 A A C A 146 A A B A 147 A AC A 148 nd nd nd nd 149 B A D B 150 A A C B 151 A A C A 152 A A C A 153nd nd nd nd 154 A A B A 155 C A D A 156 nd nd C nd 157 A A C A 158 A A CA 159 A A B A 160 A A A A 161 C C D C 162 B A C A 163 A A C A 164 A nd CB 165 C B D C 168 A A B A 169 C A D A 170 A A B A 171 A A B A 172 A A AA 173 A A B A 174 B A C A 175 A A B A 176 A A B A 177 A A B A 178 A A AA 179 A A A A 180 A A C A 181 A A C A

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference. In case of conflict, the present application, including anydefinitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject disclosure have beendiscussed, the above specification is illustrative and not restrictive.Many variations of the disclosure will become apparent to those skilledin the art upon review of this specification and the claims below. Thefull scope of the disclosure should be determined by reference to theclaims, along with their full scope of equivalents, and thespecification, along with such variations.

1-30. (canceled)
 31. A method of treating cancer, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of Formula (I):

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof, wherein: Q is CH; Z is CR₅; Xis a 5-membered heteroarylene selected from the group consisting of

wherein * indicates the point of attachment of X to the methylene groupbonded to X and/Y; Y is a 5-membered heteroarylene selected from thegroup consisting of

wherein * indicates the point of attachment of Y to the methylene groupbonded to X and Y; R₁ is selected from the group consisting of H,methyl, and hydroxymethyl; each instance of R₂ is independently selectedfrom the group consisting of H, CN, halo, C₁₋₄ alkoxy, C₁₋₄ alkyl,halo-C₁₋₄ alkyl, C₃₋₄ cycloalkylmethyl, C₃₋₆ cycloalkyl, and C₃₋₆heterocyclyl; each instance of R₃ is independently selected from thegroup consisting of H, halo, CN, C₁₋₄ alkoxy, halo-C₁₋₄ alkyl, and C₁₋₄alkyl; and each of R₄ and R₅ is independently H or F.
 32. The method ofclaim 31, wherein the compound is a compound of Formula (I-B):

or a pharmaceutically acceptable salt thereof.
 33. The method of claim32, wherein each instance of R₂ is independently selected from the groupconsisting of H, chloro, fluoro, CN, methyl, ethyl, isopropyl, methoxy,trifluoromethyl, 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, andoxetanyl.
 34. The method of claim 33, wherein each instance of R₃ isindependently selected from the group consisting of H, fluoro, chloro,bromo, CN, methoxy, difluoromethyl, trifluoromethyl, methyl, and ethyl.35. The method of claim 34, wherein R₄ is F.
 36. The method of claim 35,wherein R₅ is H.
 37. The method of claim 32, wherein the cancer is asolid tumor.
 38. The method of claim 37, wherein the cancer is lungcancer, glioblastoma, inflammatory myofibroblastic tumor (IMT), bileduct cancer, ovarian cancer, gastric cancer, colorectal cancer,angiosarcoma, melanoma, epithelioid hemangioendothelioma, esophagealcancer, kidney cancer, breast cancer, colon cancer, thyroid cancer,spitzoid tumor, or neuroblastoma.
 39. The method of claim 38, whereinthe cancer is lung cancer.
 40. The method of claim 39, wherein the lungcancer is non-small cell lung cancer.
 41. The method of claim 32,wherein the cancer is a ROS1 positive cancer.
 42. The method of claim41, wherein the ROS1 positive cancer has G2032R mutation.
 43. The methodof claim 32, wherein the cancer is a ALK positive cancer.
 44. The methodof claim 43, wherein the ALK positive cancer has G1202R mutation. 45.The method of claim 32, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 46. The method of claim32, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 47. The method of claim32, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 48. The method of claim32, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 49. The method of claim32, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 50. The method of claim32, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 51. The method of claim32, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 52. The method of claim32, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 53. The method of claim32, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 54. The method of claim32, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 55. The method of claim32, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 56. The method of claim32, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 57. A method of treatingcancer, comprising administering to a subject in need thereof apharmaceutical composition comprising (i) a compound of Formula (I), oran enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof:

and (ii) a pharmaceutically acceptable carrier or excipient; wherein Qis CH; Z is CR₅; X is a 5-membered heteroarylene selected from the groupconsisting of

wherein * indicates the point of attachment of X to the methylene groupbonded to X and Y; Y is a 5-membered heteroarylene selected from thegroup consisting of

wherein * indicates the point of attachment of Y to the methylene groupbonded to X and Y; R₁ is selected from the group consisting of H,methyl, and hydroxymethyl; each instance of R₂ is independently selectedfrom the group consisting of H, CN, halo, C₁₋₄ alkoxy, C₁₋₄ alkyl,halo-C₁₋₄ alkyl, C₃₋₄ cycloalkylmethyl, C₃₋₆ cycloalkyl, and C₃₋₆heterocyclyl; each instance of R₃ is independently selected from thegroup consisting of H, halo, CN, C₁₋₄ alkoxy, halo-C₁₋₄ alkyl, and C₁₋₄alkyl; and each of R₄ and R₅ is independently H or F.
 58. The method ofclaim 57, wherein the compound is a compound of Formula (I-B):

or a pharmaceutically acceptable salt thereof.
 59. A method forselectively inhibiting ROS1 over TRK, wherein the inhibition takes placein a subject suffering from cancer, said method comprising administeringan effective amount of a compound of Formula (I):

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof to said subject, wherein: Q isCH; Z is CR₅; X is a 5-membered heteroarylene selected from the groupconsisting of

wherein * indicates the point of attachment of X to the methylene groupbonded to X and Y; Y is a 5-membered heteroarylene selected from thegroup consisting of

wherein * indicates the point of attachment of Y to the methylene groupbonded to X and Y; R₁ is selected from the group consisting of H,methyl, and hydroxymethyl; each instance of R₂ is independently selectedfrom the group consisting of H, CN, halo, C₁₋₄ alkoxy, C₁₋₄ alkyl,halo-C₁₋₄ alkyl, C₃₋₄ cycloalkylmethyl, C₃₋₆ cycloalkyl, and C₃₋₆heterocyclyl; each instance of R₃ is independently selected from thegroup consisting of H, halo, CN, C₁₋₄ alkoxy, halo-C₁₋₄ alkyl, and C₁₋₄alkyl; and each of R₄ and R₅ is independently H or F.
 60. A method ofdecreasing a level of ROS1 or ALK in a cell, comprising contacting thecell with a compound of Formula (I):

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof, wherein: Q is CH; Z is CR₅; Xis a 5-membered heteroarylene selected from the group consisting of

wherein * indicates the point of attachment of X to the methylene groupbonded to X and Y; Y is a 5-membered heteroarylene selected from thegroup consisting of

wherein * indicates the point of attachment of Y to the methylene groupbonded to X and Y; R₁ is selected from the group consisting of H,methyl, and hydroxymethyl; each instance of R₂ is independently selectedfrom the group consisting of H, CN, halo, C₁₋₄ alkoxy, C₁₋₄ alkyl,halo-C₁₋₄ alkyl, C₃₋₄ cycloalkylmethyl, C₃₋₆ cycloalkyl, and C₃₋₆heterocyclyl; each instance of R₃ is independently selected from thegroup consisting of H, halo, CN, C₁₋₄ alkoxy, halo-C₁₋₄ alkyl, and C₁₋₄alkyl; and each of R₄ and R₅ is independently H or F.
 61. A method forselectively inhibiting ALK over TRK, wherein the inhibition takes placein a subject suffering from cancer, said method comprising administeringan effective amount of a compound of Formula (I):

or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof to said subject, wherein: Q isCH; Z is CR₅; X is a 5-membered heteroarylene selected from the groupconsisting of

wherein * indicates the point of attachment of X to the methylene groupbonded to X and Y; Y is a 5-membered heteroarylene selected from thegroup consisting of

wherein * indicates the point of attachment of Y to the methylene groupbonded to X and Y; R₁ is selected from the group consisting of H,methyl, and hydroxymethyl; each instance of R₂ is independently selectedfrom the group consisting of H, CN, halo, C₁₋₄ alkoxy, C₁₋₄ alkyl,halo-C₁₋₄ alkyl, C₃₋₄ cycloalkylmethyl, C₃₋₆ cycloalkyl, and C₃₋₆heterocyclyl; each instance of R₃ is independently selected from thegroup consisting of H, halo, CN, C₁₋₄ alkoxy, halo-C₁₋₄ alkyl, and C₁₋₄alkyl; and each of R₄ and R₅ is independently H or F.